Search

Stimuli-responsive nanoplatforms have been popular in controlled drug delivery research because of their ability to differentiate the tumor microenvironment from the normal tissue environment in a spatiotemporally controllable manner. The synergistic therapeutic approach of combining cancer chemotherapy with photothermal tumor ablation has improved the therapeutic efficacy of cancer therapeutics. In this study, a UiO-66 metal organic framework (MOF)-based system loaded with doxorubicin (DOX), surface decorated with the photothermal agents indocyanine green (ICG) and polydopamine (PDA), and conjugated with transferrin (TF) was successfully designed to operate as a responsive system to pH changes, featuring photothermal capabilities and target specificity for the purpose of treating breast cancer. The synthesized nanoplatform benefits from its uniform size, excellent DOX encapsulation efficiency (91.66 %), and efficient pH/NIR-mediated controlled release of the drug. In vitro photothermal studies indicate excellent photothermal stability of the formulation even after 6 on-off cycles of NIR irradiation. The in vitro cytotoxicity assessment using an NIR laser (808 nm) revealed that the DOX-loaded functionalized UiO-66 nanocarriers had outstanding inhibitory effects on 4T1 cells because of synergistic chemo-photo therapies, with no substantial toxicity by the carriers. In addition, cellular uptake evaluations revealed that UiO-DOX-ICG@PDA-TF could specifically target 4T1 cells on the basis of receptor-mediated internalization of transferrin receptors. Additionally, in vivo toxicity studies in Wistar rats indicated no signs of significant toxicity. The UiO-based nanoformulations effectively inhibited and destroyed cancer cells under 808 nm laser irradiation because of their minimal toxicity, strong biocompatibility, and outstanding synergistic chemo/photothermal/photodynamic treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The fabrications of hollow microcapsules (MCs) with new architecture and ability to incorporate different nanomaterials have received great interest for targeted cancer therapy. Recently, CuS based nanomaterials have been demonstrated to possess the ability to mimic Fenton-like activity in tumor environment and inducing cancer cell apoptosis by generating highly reactive oxygen species (ROS). In this study, we have developed poly(allylamine) hydrochloride (PAH)/dextran sulfate (DS) polyelectrolyte MCs capable of carrying doxorubicin (DOX) for targeted cancer therapy and ultrasound imaging. The electron microscopy investigations showed the formation of polymeric MCs of 3 µm in size with incorporated CuS NRs in their interior structure. The surface modification of MCs with folic acid (FA), and encapsulation of model hydrophilic molecules in MCs was studied by UV-Visible (UV-Vis) spectroscopy, Fourier transform infra-red (FTIR) spectroscopy and confocal laser scanning microscopy. The encapsulation efficiency of DOX was found to be 56 % and the release was found to be linear at pH 5.5 and 7.4 in the absence of ultrasound exposure. The ultrasound exposure resulted in sudden rupture of MCs at 1 MHz and 1 W/cm 2 and caused burst release of DOX at both pH conditions. The FA decorated PAH/DS/CuS NR MCs exhibited improved anti-cancer activity against MDA-MB-231 cancer cells due to the synergistic effects of ultrasound mediated burst release of chemotherapeutic drug (DOX), glutathione-stimulated ROS and targeted cancer therapy. Further, the capsules showed better echogenicity than that of control PAH/DS MCs when imaged under medical ultrasound-scanning system. Hence, the MCs demonstrated in this study have huge potential for targeted cancer theranostics by offering an option to image the cancer cells during the treatment period., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Nanomedicines comprise multiple components, and particle density is considered an important property that regulates the biodistribution of administered nanomedicines. The density of nanoparticles is characterized by centrifugal methods, such as analytical ultracentrifugation. Particle size and distribution are key physicochemical and quality attributes of nanomedicines. In this study, we developed a novel profiling method applicable to liposomes and lipid nanoparticles (LNPs), based on particle size and density, using centrifugal field-flow fractionation (CF3). We evaluated the elution profiles of PEGylated liposomes of different sizes with various doxorubicin (DOX)-loading amounts using CF3. This method was applied to evaluate the drug release of DOX-loaded liposomes, intra- and inter-batch variability, reconstitution reproducibility of AmBisome®, and elution characteristics of LNPs in COVID-19 vaccines (Comirnaty® and Spikevax TM ). The data obtained in the present study underscore the significance of the proposed methodology and highlight the importance of profiling and characterizing liposomes and LNPs using CF3 fractograms and a multi-angle light-scattering detector., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Eiichi Yamamoto reports financial support was provided by Japan Agency for Medical Research and Development. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper]., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The potential of camel milk-derived exosomes (CMDE) to enhance the bioavailability of Cannabidiol (CBD) was investigated. CBD-CMDE formulation was prepared using an established procedure and its particle size was 138.4 ± 4.37 nm, and CBD entrapment efficiency of 56.56 ± 4.26 %. In-vitro release studies showed release of 78.27 ± 5.37 % and 46.42 ± 4.75 % CBD from CMDE and control CBD formulation respectively in pH 6.8 at 24 hr. The apparent permeability (Papp) of CBD-CMDE was found to be enhanced by 3.95-fold with Papp of 22.9*10 -6  ± 0.34 cm/sec as compared to control CBD formulation with Papp of 5.8*10 -6  ± 0.65 cm/sec in MDCK cells. CBD-CMDE was found to be more potent than CBD in 2D cytotoxicity assay with IC 50 values of 3.6 ± 0.54 µM, 3.88 ± 0.54 µM and 7.53 ± 0.59 µM, 7.53 ± 0.59 µM against Doxorubicin (DOX) resistant MDA-MB-231 and Rapamycin (RM) resistant MDA-MB-468 breast cancer cells respectively. Moreover, 3D spheroids assay results demonstrated CBD-CMDE with IC 50 values of 14 ± 0.85 µM, 15 ± 0.07 µM as compared to CBD alone with IC 50 values of 25 ± 0.93 µM, 34.7 ± 0.08 µM in MDA-MB-231 DOX RT cells and MDA-MB-468 RM RT cells respectively. In-vivo PK studies showed enhanced bioavailability of CBD from CBD-exosomes with AUC (0-24h) of 1350.56 ± 187.50 h.ng/mL as compared to CBD control formulation with AUC (0-24h) of 351.95 ± 39.10 h.ng/mL with a single oral dose of 12 mg/kg. The data indicate that CMDE significantly improved the oral bioavailability of CBD. Overall, CMDE can be used to enhance the oral absorption of poorly bioavailable APIs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Currently, Non-Hodgkin Lymphoma (NHL) constitutes 85-90 % of all lymphomas. Clinical treatment of NHL is based on the "4-drug regimen" known as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone). Rituximab (RTX) is added to increase the effectiveness and selectivity of the treatment and is the first-line standard treatment for NHL patients. However, success is often prevented by the development of drug resistance. In this study, it was aimed to overcome drug resistance by using two novel tumor-targeted derivatives: guanidine-amphiphilic cyclodextrin (ACD) and guanidine-cyclodextrin polymer (PCD) nanoparticles (NP). These constructs display promise in overcoming drug resistance and enhancing the effectiveness of R-CHOP treatment while potentially eliminating the need for corticosteroid. NP were found to be smaller than 200 nm by dynamic light scattering (DLS). Hemolytic activity and cytotoxicity data on L929 cells demonstrated the safety of the newly synthesized CD derivatives. Additional in vitro characterization studies, including surface charge, physical stability, drug loading capacity, drug release profile, and imaging, as well as conventional and 3D cell culture studies were carried out. Compared to drug solutions, the viability of Daudi human lymphoma cells was statistically significantly decreased in both drug-loaded ACD and PCD NP formulations (p < 0.05). Additionally, RTX-conjugated and drug-loaded ACD NPs exhibited the lowest cell viability due to RTX dependent cytotoxicity., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Erem Bilensoy reports financial support was provided by Scientific and Technological Research Council of Turkey. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Liposomes constitute a widespread drug delivery platform, gaining more and more attention from the pharmaceutical industry and process development scientists. Their large-scale production as medicinal products for human use is all but trivial, especially when parenteral administration is required. In this study an off-the-shelf microfluidic system and a methodological approach are presented for the optimization, validation and scale-up of highly monodisperse liposomes manufacturing. Starting from a Doxil®-like formulation (HSPC, MPEG-DSPE and cholesterol), a rational approach (Design of Experiments, DoE) was applied for the screening of the process parameters affecting the quality attributes of the product (mainly size and polydispersity). Additional DoEs were conducted to determine the effect of critical process parameters "CPPs" (cholesterol concentration, total flow rate "TFR" and flow rate ratio "FRR"), thus assessing the formulation and process robustness. A scale-up was then successfully accomplished. The procedure was applied to a Marqibo®-like formulation as well (sphingomyelin and cholesterol) to show the generality of the proposed formulation, process development and scale-up approach. The application of the system and method herein presented enables the large-scale manufacturing of liposomes, in compliance with the internationally recognized regulatory standards for pharmaceutical development (Quality by Design)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

A sodium alginate (Alg) based REDOX (reduction and oxidation)-responsive and fluorescent active microgel was prepared via water in oil (w/o) mini-emulsion polymerization technique. Here, we initially synthesized sodium alginate-based disulfide cross linked microgels and after that those microgels were tagged with rhodamine amine derivative (RhB-NH 2 ) by ionic interaction to get the pH-responsive fluorescent property. Functionalized microgels were characterized using 1 H NMR, FTIR, DLS, HRTEM, FESEM, UV-vis, and fluorescence spectroscopy analyses. Presence of the REDOX-responsive disulfide-containing crosslinkers in the microgels enhances the release of doxorubicin (DOX), an anti-cancer drug in the reducing environment of the cancer-cells (simulated). Existence of the rhodamine-amine derivative in the microgels triggers the pH-dependent fluorescence property by showing fluorescence emission at 560-580 nm at pH 5.5 (cancer cell pH). The cytotoxicity of the biopolymer based microgel was assessed over both cancerous HeLa (IC 50 100 µg/mL) and non-cancerous MDCK (IC 50 200 µg/mL) cells by MTT assay which showed the synthesized microgel is non-toxic whereas DOX-loaded microgels showed significant toxicity. FACS and cell uptake (in vitro) analyses were conducted to understand the cell apoptosis cycle and behavior of the cancer cells in presence of the DOX-loaded microgels. This pH-responsive fluorescent active alginate-based biomaterial could be a promising material for the anti-cancer drug delivery and other medical fields., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cancer is the second most deadly disease worldwide, and the most traditional approaches such as chemotherapy still face limitations associated to drug dosage and off-target side effects. To address these issues, we propose the simultaneous administration of 4-Nitrochalcone (4NC) and Doxorubicin (DOX) using beeswax based nanostructured lipid carriers (NLCs). The co-encapsulation of 4NC and DOX in the beeswax based NLCs was performed using the water/oil/water double emulsion technique in association with the melt dispersion approach. The system composed by semi-spherical NLCs with an average diameter around 200 nm and narrow size distribution, displayed colloidal stability before and after redispersion, keeping the zeta potential below -30 mV. The antitumor activity of the nanoparticles was screened on different tumor cell lines, and the induced cellular death and internal ROS levels were analyzed on hepatocarcinoma cells, which were found to be more affected by the combination of 4NC and DOX. The results indicated that 4NC + DOX-NCLs could promote cytotoxicity and oxidative damage-mediated apoptosis in a HepG-2 cell line., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The combination of chemotherapy and ferroptosis therapy can greatly improve the efficiency of tumor treatment. However, ferroptosis-based therapy is limited by the unsatisfactory Fenton activity and insufficient H 2 O 2 supply in tumor cells. In this work, a nano-drug delivery system Cur@DOX@MOF-199 NPs was constructed to combine ferroptosis and apoptosis by loading curcumin (Cur) and doxorubicin (DOX) based on the copper-based organic framework MOF-199. Cur@DOX@MOF-199 NPs decompose quickly by glutathione (GSH), releasing Cu 2+ , DOX and Cur. Cu 2+ can deplete GSH while also being reduced to Cu + ; DOX can induce apoptosis and simultaneously boost H 2 O 2 production. Moreover, Cur enhanced the expression of intracellular heme oxygenase-1 (HO-1), for decomposing heme and releasing Fe 2+ , which further combined with Cu + to catalyze H 2 O 2 for hydroxyl radical (OH) generation, leading to the accumulation of lipid peroxide and ferroptosis. As a result, Cur@DOX@MOF-199 NPs exhibited significantly enhanced antitumor efficacy in MCF-7 tumor-bearing mouse model, suggesting this nano formulation is an excellent synergetic pathway for apoptosis and ferroptosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

pH-responsive polymeric micelles have been extensively studied for nanomedicine and take advantage of pH differentials in tissues for the delivery of large doses of cytotoxic drugs at specific target sites. Despite significant advances in this area, there is a lack of versatile and adaptable strategies to render micelles pH-responsive that could be widely applied to different payloads and applications. To address this deficiency, we introduce the concept of oligoelectrolyte-mediated, pH-triggered release of hydrophobic drugs from non-responsive polymeric micelles as a highly effective approach with broad scope. Herein, we investigate the influence of the oligoelectrolyte, oligo(2-vinyl pyridine) (OVP), loading and polymer molecular weight on the pH-sensitivity, drug loading/release and cytotoxicity of poly(ethylene glycol-b-ε-caprolactone) (PEG-b-PCL) micelles using copolymers with either short or long hydrophobic blocks (PEG 4 PCL 4 and PEG 10 PCL 10 , respectively). The micelles were characterized as a function of pH (7.4 to 3.5). Dynamic light scattering (DLS) revealed narrow particle size distributions (PSDs) for both the blank and OVP-loaded micelles at pH 7.4. While OVP encapsulation resulted in an increase in the hydrodynamic diameter (D h ) (cf. blank micelles), a decrease in the pH below 6.5 led to a decrease in the D h consistent with the ionization and release of OVP and core collapse, which were further supported by proton nuclear magnetic resonance ( 1 H NMR) spectroscopy and UV-visible (UV-vis) spectrophotometry. The change in zeta potential (ζ) with pH for the OVP-loaded PEG 4 PCL 4 and PEG 10 PCL 10 micelles was different, suggesting that the location/distribution of OVP in the micelles is influenced by the polymer molecular weight. In general, co-encapsulation of drugs (doxorubicin (DOX), gossypol (GP), paclitaxel (PX) or 7-ethyl-10-hydroxycamptothecin (SN38)) and OVP in the micelles proceeded efficiently with high encapsulation efficiency percentages (EE%). In vitro release studies revealed the rapid, pH-triggered release of drugs from OVP-loaded PEG 10 PCL 10 micelles within hours, with higher OVP loadings providing faster and more complete release. In comparison, no triggered release was observed for the OVP-loaded PEG 4 PCL 4 micelles, implying a strong molecular weight dependency. In metabolic assays the drug- and OVP-loaded PEG 10 PCL 10 micelles were found to result in significant enhancement of the cytotoxicity compared to drug-loaded micelles (no OVP) or other controls. Importantly, micelles with low OVP loadings were found to be nearly as effective as those with high OVP loadings. These results provide key insights into the tunability of the oligoelectrolyte-mediated approach for the effective formulation of pH-responsive micelles and pH-triggered drug release., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Doxorubicin (DOX) is a chemotherapy drug used for hepatocellular carcinoma (HCC) treatment, but its effectiveness can be dramatically dampened by cancer cell chemoresistance. Signal transducer and activator of transcription 3 (STAT3) is implicated with drug resistance in a range of cancers (e.g., HCC), and the STAT3 inhibition can reverse the resistance of cancer cells to chemotherapeutic drugs. In the present study, a combination regimen to improve the efficiency of DOX was provided via the STAT3 blockade using plumbagin (PLB). A poly(lactic-co-glycolic acid) decorated by polyethylene glycol and aminoethyl anisamide was produced in the present study with the hope of generating the nanoparticles for co-delivery of DOX and PLB. The resulting co-formulation suppressed the STAT3 activity and achieved the synergistic chemotherapy, which led to tumor inhibition in the mice with subcutaneous DOX-resistant HCC, without causing any toxicity. The present study reveals the synergism of DOX and PLB, and demonstrates a promising combinatorial approach for treating HCC., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Shulan Han reports financial support was provided by Jilin Provincial Science and Technology Department. Zhuo Yu reports financial support was provided by National Natural Science Foundation of China. Jianfeng Guo reports financial support was provided by Jilin Provincial Science and Technology Department. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The main treatment modalities for breast cancer include surgery, chemotherapy, and radiotherapy, and each treatment will bring different side effects. Design and synthesizing a novel nanostructure for chemo-radiotherapy has been proposed as an effective method in consideration to enhance the drug efficiency as well as improve the effect of radiotherapy. This study aimed to synthesize zinc nanoparticles (ZnNPs) coated with alginate conjugated with Doxorubicin (Dox) drug and investigate its effects along with X-irradiation on MDA-MB-231 triple-negative breast cancer cell line. ZnNPs coated with alginate were synthesized and conjugated to Dox by covalent bonding and characterized using various physicochemical tests. A hemolysis test was used to assess blood biocompatibility. The radiosensitization properties and anti-cancer effects of the synthesized nanostructures were tested by cell uptake, cell viability, apoptosis, cell cycle, and scratch assays with and without radiation exposure. The physicochemical characterization results showed that the synthesis of nanostructures was successfully carried out. The obtained results from the cell uptake assay showed the effective absorption of nanostructures by the cells. The Zn@Alg-Dox NPs significantly reduced cell growth, increased apoptosis, inhibited cell migration, and led to the arrest of different cell cycle phases in both conditions with and without X-ray exposure. Coating ZnNPs with alginate and Doxorubicin conjugation leads to an increase the radiation sensitivity in radiotherapy as well as therapeutic efficiency. Therefore, Zn@Alg-Dox NPs can be used as radiosensitizing nanomedicine for in vivo studies in the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Doxorubicin (DOX) is a chemotherapeutic drug used in osteosarcoma treatments, usually administrated in very high dosages. This study proposes novel DOX microcarriers based on chitosan (CHT) physically crosslinked with copper(II) ions that will act synergically to inhibit tumor growth at lower drug dosage without affecting the healthy cells. Spherical CHT-Cu microparticles with a smooth surface and an average size of 30.1 ± 9.1 µm were obtained by emulsion. The release of Cu 2+ ions from the CHT-Cu microparticles showed that 99.4 % of added cupric ions were released in 72 h of incubation in a complete cell culture medium (CCM). DOX entrapment in microparticles was conducted in a phosphate buffer solution (pH 6), utilizing the pH sensitivity of the polymer. The successful drug-loading process was confirmed by DOX emitting red fluorescence from drug-loaded microcarriers (DOX@CHT-Cu). The drug release in CCM showed an initial burst release, followed by sustained release. Biological assays indicated mild toxicity of CHT-Cu microparticles on the MG-63 osteosarcoma cell line, without affecting the viability of human mesenchymal stem cells (hMSCs). The DOX@CHT-Cu microparticles at concentration of 0.5 mg mL ‒ 1 showed selective toxicity toward MG-63 cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Two frequent problems hindering clinical translation of nanomedicine are low drug loading and low colloidal stability. Previous efforts to achieve ultrahigh drug loading (>30 %) introduce new hurdles, including lower colloidal stability and others, for clinical translation. Herein, we report a new class of drug nano-carriers based on our recent finding in protein-nanoparticle co-assembly supraparticle (PNCAS), with both ultrahigh drug loading (58 % for doxorubicin, i.e., DOX) and ultrahigh colloidal stability (no significant change in hydrodynamic size after one year). We further show that our PNCAS-based drug nano-carrier possesses a built-in environment-responsive drug release feature: once in lysosomes, the loaded drug molecules are released instantly (<1 min) and completely (∼100 %). Our PNCAS-based drug delivery system is spontaneously formed by simple mixing of hydrophobic nanoparticles, albumin and drugs. Several issues related to industrial production are studied. The ultrahigh drug loading and stability of DOX-loaded PNCAS enabled the delivery of an exceptionally high dose of DOX into a mouse model of breast cancer, yielding high efficacy and no observed toxicity. With further developments, our PNCAS-based delivery systems could serve as a platform technology to meet the multiple requirements of clinical translation of nanomedicines., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Most nanomedicines with suitable sizes (normally 100-200 nm) exhibit favorable accumulation in the periphery of tumors but hardly penetrate into deep tumors. Effective penetration of nanomedicines requires smaller sizes (less than 30 nm) to overcome the elevated tumor interstitial fluid pressure. Moreover, integrating an efficient diagnostic agent in the nanomedicines is in high demand for precision theranostics of tumors. To this end, a near-infrared light (NIR) -triggered size-shrinkable micelle system (Fe 3 O 4 @AuNFs/DOX-M) coloaded antitumor drug doxorubicin (DOX) and biomodal imaging agent magnetic gold nanoflower (Fe 3 O 4 @AuNFs) was developed to achieve efficient theranostic of tumors. Upon the accumulation of Fe 3 O 4 @AuNFs/DOX-M in the tumor periphery, a NIR laser was irradiated near the tumor sites, and the loaded Fe 3 O 4 @Au NFs could convert the light energy to heat, which triggered the cleavage of DOX-M to the ultra-small micelles (∼5 nm), thus realizing the deep penetration of micelles and on-demand drug release. Moreover, Fe 3 O 4 @AuNFs in the micelles could also be used as CT/MRI dual-modal contrast agent to "visualize" the tumor. Up to 92.6 % of tumor inhibition was achieved for the developed Fe 3 O 4 @AuNFs/DOX-M under NIR irradiation. This versatile micelle system provided a promising drug carrier platform realizing efficient tumor dual-modal diagnosis and photothermal-chemotherapy integration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Doxorubicin hydrochloride (DOX) is an anticancer agent used in cancer chemotherapy. The purpose of this study was to design nanostructured lipid carriers (NLCs) of DOX as smart chemotherapy to improve its photostability and anticancer efficacy. The characteristics of DOX and DOX-loaded NLCs were investigated using UV-Vis spectroscopy, Fourier transform infrared (FTIR) spectroscopy, particle size, and zeta potential study. The cytotoxicity of DOX was evaluated against three cancer cell lines (HeLa, A549, and CT-26). The particle size and zeta potential were in the range 58.45-94.08 nm and -5.80 mV - -18.27 mV, respectively. The chemical interactions, particularly hydrogen bonding and van der Waals forces, between DOX and the main components of NLCs was confirmed by FTIR. NLCs showed the sustained release profile of DOX. The photostability results revealed that the NLC system improved the photostability of DOX. Cytotoxicity results using the three cell lines showed that all formulations improved the anticancer efficacy of free DOX, and the efficacy was dependent on cell type and particle size. These results suggest that DOX-loaded NLCs are promising chemotherapeutic agents for cancer treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

We developed cyclic RGD-tagged polymeric micellar nanoassemblies for sustained delivery of Doxorubicin (Dox) endowed with significant cytotoxic effect against MG63, SAOS-2, and U2-OS osteosarcoma cells without compromising the viability of healthy osteoblasts (hFOBs). Targeted polymeric micellar nanoassemblies (RGD-NanoStar@Dox) enabled Dox to reach the nucleus of MG63, SAOS-2, and U2-OS cells causing the same cytotoxic effect as free Dox, unlike untargeted micellar nanoassemblies (NanoStar@Dox) which failed to reach the nucleus and resulted ineffective, demonstrating the crucial role of cyclic RGD peptide in driving cellular uptake and accumulation mechanisms in osteosarcoma cells. Micellar nanoassemblies were obtained by nanoformulation of three-armed star PLA-PEG copolymers properly synthetized with and without decoration with the cyclic-RGDyK peptide (Arg-Gly-Asp-D-Tyr-Lys). The optimal RGD-NanoStar@Dox nanoformulation obtained by nanoprecipitation method (8 % drug loading; 35 % encapsulation efficiency) provided a prolonged and sustained drug release with a rate significantly lower than the free drug under the same experimental conditions. Moreover, the nanosystem preserved Dox from the natural degradation occurring under physiological conditions (i.e., dimerization and consequent precipitation) serving as a slow-release "drug reservoir" ensuring an extended biological activity over the time., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

The application of polymer-based drug delivery systems is advantageous for improved pharmacokinetics, controlled drug release, and decreased side effects of therapeutics for inflammatory disease. Herein, we describe the synthesis and characterization of linear N-(2-hydroxypropyl)methacrylamide-based polymer conjugates designed for controlled release of the anti-inflammatory drug dexamethasone through pH-sensitive bonds. The tailored release rates were achieved by modifying DEX with four oxo-acids introducing reactive oxo groups to the DEX derivatives. Refinement of reaction conditions yielded four well-defined polymer conjugates with varied release profiles which were more pronounced at the lower pH in cell lysosomes. In vitro evaluations in murine peritoneal macrophages, human synovial fibroblasts, and human peripheral blood mononuclear cells demonstrated that neither drug derivatization nor polymer conjugation affected cytotoxicity or anti-inflammatory properties. Subsequent in vivo tests using a murine arthritis model validated the superior anti-inflammatory efficacy of the prepared DEX-bearing conjugates with lower release rates. These nanomedicines showed much higher therapeutic activity compared to the faster release systems or DEX itself., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Mastering new and efficient ways to obtain successful drug delivery systems (DDS) with controlled release became a paramount quest in the scientific community. Increase of malignant bone tumors and the necessity to optimize an approach of localized drug delivery require research to be even more intensified. Octacalcium phosphate (OCP), with a number of advantages over current counterparts is extensively used in bone engineering. The aim of the present research was to synthesize bioactive and biocompatible doxorubicin (DOX) containing OCP particles. DOX-OCP was successfully obtained in situ in an exhaustive range of added drug (1-20 wt%, theoretical loading). Based on XRD, above 10 wt% of DOX, OCP formation was inhibited and the obtained product was low crystalline α-TCP. In-vitro drug release was performed in pH 7.4 and 6.0. In both pH environments DOX had a continuous release over six weeks. However, the initial drug burst for pH 7.4, in the first 24 h, ranged from 15.9 ± 1.3 % to 33.5 ± 12 % and for pH 6.0 23.7 ± 1.5 % to 36.2 ± 12 %.The DOX-OCP exhibited an inhibitory effect on viability of osteosarcoma cell lines MG63, U2OS and HOS. In contrast, MC3T3-E1 cells (IC50 > 0.062 µM) displayed increased viability and proliferation from 3rd to 7th day. Testing of the DDS on ferroptotic markers (CHAC1, ACSL4 and PTGS2) showed that OCP-DOX does not induce ferroptotic cell death. Moreover, the evaluation of protein levels of cleaved PARP, by western blotting analysis, corroborated that apoptosis is the main pathway of programmed cell death in osteosarcoma cells induced by DOX-OCP., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Nanomaterials' application in cancer therapy has been driven by their ability to encapsulate chemotherapeutic drugs as well as to reach the tumor site. Nevertheless, nanomedicines' translation has been limited due to their lack of specificity towards cancer cells. Although the nanomaterials' surface can be coated with targeting ligands, such has been mostly achieved through non-covalent functionalization strategies that are prone to premature detachment. Notwithstanding, cancer cells often establish resistance mechanisms that impair the effect of the loaded drugs. This bottleneck may be addressed by using near-infrared (NIR)-light responsive nanomaterials. The NIR-light triggered hyperthermic effect generated by these nanomaterials can cause irreversible damage to cancer cells or sensitize them to chemotherapeutics' action. Herein, a novel covalently functionalized targeted NIR-absorbing nanomaterial for cancer chemo-photothermal therapy was developed. For such, dopamine-reduced graphene oxide nanomaterials were covalently bonded with hyaluronic acid, and then loaded with doxorubicin (DOX/HA-DOPA-rGO). The produced nanomaterials showed suitable physicochemical properties, high encapsulation efficiency, and photothermal capacity. The in vitro studies revealed that the nanomaterials are cytocompatible and that display an improved uptake by the CD44-overexpressing breast cancer cells. Importantly, the combination of DOX/HA-DOPA-rGO with NIR light reduced breast cancer cells' viability to just 23 %, showcasing their potential chemo-photothermal therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Multifunctional drug delivery platforms represent ideal approaches to reliably targeting pharmacological agents of interest to the complex tumor microenvironment (TME), yet the complicated synthesis processes, high costs, and toxicities associated with these agents have hindered their clinical application to date. In this study, the properties of the TME are leveraged to develop a multifunctional pNAB/AS DNA microgel that is able to actively target tumors. This microgel is generated by a straightforward one-step free radical precipitation polymerization procedure, exhibiting extremely high drug encapsulation efficiency (∼90%), and is responsive to three environmental stimuli including temperature, reduction, and an acidic pH while showing minimal drug leakage under physiological conditions. Through a synergistic combination of appropriate size and aptamer recognition, this microgel is able to reliably facilitate intratumoral drug accumulation and nuclear drug delivery. Critically, pNAB/AS-Dox treatment is associated with specific antitumor activity in vitro and in vivo while retaining a good biosafety profile and causing lower levels of off-target toxicity as compared to free drug treatment. Together, these findings emphasize the potential value of this multifunctional pNAB/AS DNA microgel as a platform amenable to targeted drug delivery to the TME, providing a foundation for further efforts to readily develop multifunctional drug delivery systems., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Melanoma cancer wound healing is critical and complex and poses a significant challenge to researchers. Drug resistance, adverse side effects, and inefficient localization of chemotherapeutic drugs limit common treatment strategies in melanoma cancer. Using drug delivery nanostructures with low side effects and high efficiency, besides having antibacterial and antiseptic properties, can effectively repair the damage caused by the disease. To this end, this study aimed to develop a drug delivery nanosystem based on doxorubicin (DOX)-loaded amine-functionalized mesoporous silica nanoparticles (MSNs), linked with green synthesized silver nanoparticles (AgNPs). Characterization methods including microscopic methods and X-ray diffraction (XRD) confirmed the synthesis and functionalization of the well-dispersed nanoparticles with nanosized and uniform structures. The poly(ε-caprolactone) (PCL) nanofibers as a strong scaffold were produced by the blow spinning method and DOX-loaded nanoparticles were blow spun on PCL nanofibers along with gelatin solution. The resulting nanosystem including nanofibers and nanoparticles (NFs/NPS) showed a fine loading percent with a proper release profile of DOX and AgNPs and low hemolysis activity. Moreover, besides preventing infection by AgNPs, the DOX-loaded NFs/NPs could effectively destroy melanoma cancer cells. The attachment of normal cells to the nanoparticles-loaded nanofibers scaffold revealed the possibility of healing wounds caused by melanoma cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

In this study, the Fe 3 O 4 nanoparticles were encapsulated in the hyperbranched poly L -lysine citramid (HBPLC). The Fe 3 O 4 -HBPLC nanocomposite modified with L -arginine and quantum dots (QDs) to obtain Fe 3 O 4 -HBPLC-Arg/QDs as a new photoluminescent and magnetic nanocarrier for the pH-responsive release and targeted delivery of Doxorubicin (DOX). The prepared magnetic nanocarrier was fully characterized using different techniques. Its various potential as a magnetic nanocarrier was evaluated. The in-vitro drug release studies exhibited that the prepared nanocomposite has pH-responsive behavior. The antioxidant study revealed good antioxidant properties of the nanocarrier. Also, the nanocomposite revealed excellent photoluminescence with a quantum yield of 48.5 %. Cellular uptake studies showed that Fe 3 O 4 -HBPLC-Arg/QD has high cell uptake in MCF-7 cells and can be used for bioimaging applications. In-vitro cytotoxicity, colloidal stability, and enzymatic degradability studies revealed that the prepared nanocarrier is non-toxic (with cell viability of 94%), stabile and biodegradable (about 37%). The nanocarrier was hemocompatible with 8% hemolysis. Also, according to the apoptosis and MTT assays, the Fe 3 O 4 -HBPLC-Arg/QD-DOX induced greater toxicity and cellular apoptosis against breast cancer cells about 47.0 %., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

In this study, we prepared a β-cyclodextrin polymer (β-CDP) co-loaded quercetin (QCT) and doxorubicin (DOX) nanocarrier (β-CDP/QD NCs) by freeze-dried method to combat P-glycoprotein (P-gp) mediated multidrug resistance (MDR) in KB-Ch R 8-5 cancer cells. Various microscopic and spectroscopic techniques were employed to characterize the prepared nanocarrier. The molecular docking studies confirm the effective binding interactions of QCT and DOX with the synthesized β-CD polymer. The in vitro drug release study illustrates the sustainable release of DOX and QCT from the β-CDP nanocarrier. Further, we noticed that the QCT released from the β-CDP nanocarrier improved the intracellular availability of DOX via modulating P-gp drug efflux function in KB-Ch R 8-5 cells and MCF-7/DOX cancer cells. Cell uptake results confirmed the successful internalization of DOX in KB-Ch R 8-5 cells compared with free DOX. Cell-based assays such as nuclear condensation, alteration in the mitochondrial membrane potential (MMP), and apoptosis morphological changes confirmed the enhanced anticancer effect of β-CDP/QD NCs in the resistant cancer cells. Hence, QCT and DOX co-loaded β-CDP may be considered effective in achieving maximum cell death in the P-gp overexpressing MDR cancer cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

This research aimed to acquire doxorubicin loaded zinc oxide nanoflowers (DOX-ZnO-NFs) for intracellular drug cargo possessing a synergistic in-vitro anticancer activity with minimal toxicity. Zinc is the main inorganic metallic component of various enzyme systems and has the possibility of fabrication into the diverse nano-structural forms. An easy absorption and extensive tissue distribution of zinc have made it unique candidate for drug delivery system. Hence, the zinc oxide nanoflowers were prepared with sonochemical-precipitation. The developed system was characterized using the reported methods and was optimized employing design of experiment, coupled with artificial neural network approach. The optimized nanoflowers (DOX-ZnO-NFV) were anionic with particle size of 24 ± 0.05 nm, polydispersity index of <0.5, a zeta potential of -25.68 ± 0.16 mV, yield of 87.40% and encapsulation efficiency of 85.25%. DOX-ZNO-NFV depicted sustained DOX release, around 65.413% release in 30 h at pH 7.4 and assumed Weibull model with its derived parameters, a and b of 22.77 and 0.918, respectively. DOX-ZnO-NFV remained stable on storage for 3 months at 4° C/50% RH and 25° C/60% RH. DOX-ZnO-NFV displayed a zone of inhibition of 13.50 ± 1.25 mm and 25.50 ± 0.98 mm, respectively against gram-positive Staphylococcus aureus and gram-negative Escherichia coli strains, presenting the nanoflowers as self-preservative. DOX-ZnO-NFV exhibited higher in-vitro anticancer activity in Henrietta Lacks cell line, with least hemolysis compared to the free DOX and ZnO-NF. Thus, doxorubicin loaded zinc oxide nanoflowers envisioned to act as better chemotherapeutic cargos with the maximize anticancer activity and minimal toxicity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The multifaceted drug carrier system is an emerging trend in delivering chemotherapeutic drugs and photosensitizers for the synergistic effect. In this work, we have designed a functionalized graphene oxide (GO) based carrier system for combined chemo-photodynamic therapeutic effects. Doxorubicin (DOX) and rose bengal (RB) were entrapped on the surface of GO via hydrophobic and π-π stacking interactions. The functional group determination, crystalline properties, surface morphology, and hydrodynamic size were evaluated using FT-IR, XRD, SEM, TEM, AFM, and DLS analysis. At 24 h, the entrapment efficiency was 65 % DOX and 40.92 % RB, and the loading capacities were 16.9 % DOX and 5.68 % RB observed at 30 min. The drug release percentage was higher in pH-2.6 rather than in pH-5.5, 6.8, and 7.4 pH environments. The in-vitro toxicity analysis using the LDH assay reveals that the DOX and RB co-loaded carriers had a significant cytotoxic effect on MCF-7 cells, indicating that the carrier could improve the therapeutic efficacy of DOX. Morphological changes were studied using inverted light microscopy; the cells were irradiated with a laser 525 nm 10 J/cm 2 for 2 min 51 sec, and it was observed that the DOX and RB co-loaded carrier with laser-irradiated cells exposed the high-level morphological changes with the occurrence of apoptotic cell death. Compared to free DOX, the DOX/RB co-loaded carrier + laser had an efficient anticancer activity, as confirmed by DAPI staining cell uptake, flow cytometry, and intracellular ROS generation analysis. The DOX and RB co-loaded carrier clearly exhibits the RB-mediated photodynamic action on MCF-7 cells in response to external laser light irradiation. It permits an on-demand dual-payload release to trigger an instantaneous photodynamic and chemo treatment for cancer cell eradication. Finally, the ensuing dual-agent release is probable to successfully fight cancer via a synergistic effect., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

A new kind of negatively charged polymer-shielded supramolecular nano-micelles with dual-responsive property was designed for tumor treatment, which was prepared on the basis of adamantane terminated linear PAsp(DIP) and disulfide-β-cyclodextrin-terminated PAsp(EDA). The supramolecular nano-micelles comprised a 2,3-dimethylmaleic anhydride (DA) protective layer to stabilize the micelles, a pH-responsive core to package hydrophobic model drugs, and a disulfide-crosslinked interlayer to shackle the core against drug leakage under normal physiological conditions. After arriving at the tumor tissue via EPR, the targeting function could be turned on by dislodging DA groups on the surface of micelles, which allowed the drug-loaded nano-micelles to be easily phagocytized by the tumor cells, and then release the drug inside the cells induced by the increased glutathione level and acidic pH. The results indicated that the charge-conversional dual-responsive supramolecular nano-micelles showed excellent antitumor activity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Commonly the directly administered chemotherapy drugs lack targeting in tumor treatment. Thus, trying to improve cancer treatment efficiency led us to design a new intelligent system for cancer treatment. Considering these, in the current work, at first, the 2-aminoterephthalic acid (NH 2 -BDC) intercalated layered double hydroxides (MgAl-(NH 2 -BDC) LDH) were synthesized simply. Afterward, the in situ growth of the iron-based metal-organic frameworks in the presence of MgAl-(NH 2 -BDC) LDH occurred (MgAl-LDH/Fe-MOF). In the end, the reaction of MgAl-LDH/Fe-MOF with D-mannose (D-Man) achieved the MgAl-LDH/Fe-MOF/D-Man ternary hybrid nanostructure. Scanning electron microscopy (SEM) and energy dispersive X-ray (EDX) analysis confirmed the formation of the monodisperse Fe-MOF with nanosize in the presence of MgAl-LDH. Importantly, methotrexate (MTX) and doxorubicin (DOX) entrapment efficiency reached respectively about 28 wt% and 21% for MgAl-LDH/Fe-MOF/D-Man. The in vitro drug release experiments revealed a higher drug release at pH 5.0 in comparison with pH 7.4 which revealed its promising potential for anticancer drug delivery applications. Bioassay results revealed that the co-drug-loaded MgAl-LDH/Fe-MOF/D-Man has higher cytotoxicity on MDA-MB 231 cells. At last, fluorescence microscopy and flow cytometric analysis confirmed the successful uptake of MgAl-LDH/Fe-MOF/D-Man into MDA-MB 231 cell lines, as well as its bioimaging potential. A survey in the published literature approved that this work is the first report on the evaluation of the MgAl-LDH/Fe-MOF/D-Man for targeted co-delivery of both MTX and DOX. Finally, results collectively demonstrate the importance of the biocompatible MgAl-LDH/Fe-MOF/D-Man as a hopeful candidate for biomedicinal applications from the targeted co-drug delivery and bioimaging potential viewpoints., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The low immunogenicity and tumor immunosuppressive microenvironment (TIM) are two major obstacles for cancer immunotherapy. Synergistically immunogenic cell death induction and tumor-associated macrophages depletion could perfectly overcome this limitation. Herein, a tumor-associated macrophage (TAMs) membrane-camouflaged pH-responsive doxorubicin (DOX) loaded hyaluronic acid (HA)-g-poly (histidine) polymeric micelles (DHP@M2) was fabricated for the first time. DHP@M2 could effectively accumulated into tumor regions via TAMs membrane mediated immune camouflage. In acidic tumor microenvironment, particle size of DHP was enlarged due to decrease hydrophobic interaction of inner core, which caused a "membrane escape effect" to expose inner HA residue. Together high expression of α4β1 integrin, DHP@M2 could reach CD44/VCAM-1 dual-targetability to facilitate intracellular DOX accumulation for efficient ICD induction. Meanwhile, TAMs membrane could absorb colony stimulating factor 1(CSF1) through high expression of its receptor (CSF1R) on TAMs membrane to deplete TAMs in tumor tissues and relieved TIM. This strategy could efficiently induce cytotoxic T lymphocyte (CTLs) infiltration for antitumor immune response and inhibit tumor progression in 4T1 tumor bearing Balb/c mice. Therefore, DHP@M2 is suitable for cancer chemotherapy-sensitized immunotherapy., (Copyright © 2022. Published by Elsevier B.V.)

Doxorubicin (DOX) is a chemotherapeutic drug that belongs to the anthracyclines family. Cardiotoxicity is one of the main limiting factor of prescribing DOX. To reduce its side effects and enhance the drug delivery to the targeted tissues, we aimed to establish a new targeted and controlled release drug delivery system for treatment of breast cancer. In this article, we tried to synthesize a new nanoplatform consisted of DOX conjugate with hydrazide and disulfide bonds to the hyaluronic acid (HA). Firstly, 4,4'-Dithiodibutyric acid (DTBH) was conjugated with HA. Then, 3-aminophenyl boronic acid monohydrate (APBA) was conjugated with DTBH-HA. Subsequently, DOX was added to DTBH-HA-APBA. HA is a natural polymer with the ability to target CD44, a cell surface adhesion receptor, which are highly overexpressed on the surface of variety of cancer cells. Other targeting agent, APBA can target sialic acid on the cancer cells surface and improve the tumor uptake. Formation of The DTBH-HA-APBA conjugate was confirmed by proton nuclear magnetic resonance ( 1 H NMR) spectroscopy. Scanning emission electron microscopy (SEM) images of the DOX-DTBH-HA-APBA displayed a spherical shape with an average diameter of about 70 nm. In vitro drug release study showed considerably different release pattern of DOX from the formulation at acidic pH (5.4) which was higher than normal pH (7.4). Cellular uptake and cellular cytotoxicity analysis were examined in human breast adenocarcinoma cell line (MCF-7) and mouse breast cancer cells (4T1) as positive cell lines and Chinese Hamster Ovary cells (CHO) as negative cell line. Results confirmed that there is a remarkable difference between dual-targeted (DOX-DTBH-HA-APBA) and single targeted (DOX-DTBH-HA) formulations in both positive cell lines regarding internalization and cytotoxicity. In vivo studies indicated that dual-targeted formulation has the best efficacy with minimum side effects in mouse model. Fluorescence imaging of organs revealed that DOX-DTBH-HA-APBA showed greater DOX accumulation compared with DOX-DTBH-HA and free DOX in tumor site. Also, pathological evaluation indicated that there is no observable cardiotoxicity with final formulation., (Copyright © 2022. Published by Elsevier B.V.)

Unimolecular micelles have attracted intense interests as drug carriers for tumor chemotherapy owing to their superior stability in comparison with the self-assembled supramolecular ones. Among them, the dendritic polymers with the polar frameworks could favour the loading of chemotherapeutic drugs rather than the hyperbranched polymers via radical polymerization, by enhancing the interaction with drugs. While the tedious synthesis procedure for dendritic polymers could be simplified with the construction principle on urethane chemistry. Here, the PEGylated dendritic polyurethanes, Ph-DPU Gly -PEG and Ph-DPU TEA -PEG, were designed with glycerol or triethanolamine as monomer, respectively. The effect of the molecular architecture of the Ph-DPU-PEGs unimolecular micelles on the controlled drug releasing performance was compared. It was found that the Ph-DPU TEA -PEG with tertiary amine as branching points could efficiently endow the pH-triggered drug release, due to its protonation., (Copyright © 2022 Elsevier B.V. All rights reserved.)

An intramolecular fluorescence resonance energy transfer (FRET)-based macromolecular theranostic prodrug was designed by directly conjugating Doxorubicin (DOX) as the FRET acceptor onto the naphthalimide side groups in the fluorescent copolymer PPEGMA 20 -PNAP 8 as the FRET energy donor via an acid-labile imine bond, without a fluorogenic linker. The proposed PPEGMA 20 -PNAP 8 -DOX theranostic prodrug showed a high DOX content of 24.3% owing to a conjugation efficiency of > 93% under mild conjugation conditions. It could easily self-assemble into unique theranostic nanoparticles with a D h of 71 nm. The theranostic nanoparticles showed excellent pH-triggered DOX release performance with very low premature drug leakage of 6.3% in normal physiological medium over 129 h, while>91% of the conjugated DOX was released in the acidic tumor intracellular microenvironment. MTT assays indicated the enhanced antitumor efficacy of the proposed theranostic nanoparticles compared with free DOX. Furthermore, because drug release was triggered by pH, orange fluorescence was restored to the blue fluorescence of the backbone copolymer. Such self-tracking pH-responsive colorful fluorescence variations during intracellular drug delivery and release are expected to allow real-time tumor intracellular drug release monitoring and imaging diagnosis., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Targeting nanocarrier drug delivery systems, that deliver drug payloads to the site of disease action, are frequently viewed as the future of nanocarrier based therapies but have struggled to breakthrough to the clinic in comparison to non-targeting counterparts. Using unilamellar liposomes as model nanocarriers, we show that cell targeting strategy (electrostatic, ligand and antigen) influences both the intracellular fate of the liposomes and the corresponding efficacy of the loaded drug, doxorubicin, in endothelial cells. We show that increased liposome uptake by cells does not translate to improved efficacy in this scenario but that liposome intracellular trafficking, particularly distribution between recycling endosomes and lysosomes, influences in vitro efficacy. Choosing targeting strategies that promote desired nanocarrier intracellular trafficking may be a viable strategy to enhance the in vivo efficacy of drug delivery systems., (Copyright © 2020. Published by Elsevier B.V.)

Manufacturing of liposomal nanomedicines (e.g. Doxil®/Caelyx®) is a challenging and slow process based on multiple-vessel and batch processing techniques. As a result, the translation of these nanomedicines from bench to bedside has been limited. Microfluidic-based manufacturing offers the opportunity to address this issue, and de-risk the wider adoption of nanomedicines. Here we demonstrate the applicability of microfluidics for continuous manufacturing of PEGylated liposomes encapsulating ammonium sulfate (250 mM). Doxorubicin was subsequently active-loaded into these pre-formed liposomes. Critical process parameters and material considerations demonstrated to influence the liposomal product attributes included solvent selection and lipid concentration, flow rate ratio, and temperature and duration used for drug loading. However, the total flow rate did not affect the liposome product characteristics, allowing high production speeds to be adopted. The final liposomal product comprised of 80-100 nm vesicles (PDI < 0.2) encapsulating ≥ 90% doxorubicin, with matching release profiles to the innovator product and is stable for at least 6 months. Additionally, vincristine and acridine orange were active-loaded into these PEGylated liposomes (≥ 90% and ~100 nm in size) using the same process. These results demonstrate the ability to produce active-loaded PEGylated liposomes with high encapsulation efficiencies and particle sizes which support tumour targeting., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Layer-by-layer (LbL) assembled poly(allylamine hydrochloride) (PAH) and poly(methacrylic acid) (PMA) microcapsules were designed to incorporate gold nanorods (NRs) and co-encapsulate and release two drugs for cancer therapy. Calcium carbonate (CaCO 3 ) microparticles modified with preformed NRs were used as sacrificial templates for the fabrication of hollow PAH/PMA/NR capsules incorporated with NRs. The hollow capsules were found to be 4.5 ± 0.5 µm in size and appeared with uniformly distributed NRs in the interior of the capsules. The morphology of the capsules transformed from pore free continuous structure to porous structure under laser light irradiation at 808 nm and 0.5 W cm -2 . The encapsulation experiments showed that the hydrophilic drug (doxorubicin hydrochloride, Dox) was encapsulated in the interior of the capsules while the hydrophobic drug (nimbin, NB) was entrapped in the porous polymeric network of the layer components. The encapsulation efficiency was found to be 30% for both Dox and NB. The release experiments showed an initial burst release followed by sustained release up to 3 h. Notably, the release was completed within 30 min under NIR irradiation at 808 nm. The estimated IC 50 values against THP-1 cells were 75 and 1.8 µM for NB and Dox, respectively. The dual drug loaded capsules showed excellent anticancer activity against THP-1 cells under NIR light exposure in in-vitro experiments. Thus, such remotely addressable dual-drug loaded capsules with the provision for encapsulation of natural drugs demonstrate high potential for use as theranostics in cancer therapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Nanomedicines are well recognised for their ability to improve therapeutic outcomes. Yet, due to their complexity, nanomedicines are challenging and costly to produce using traditional manufacturing methods. For nanomedicines to be widely exploited, new manufacturing technologies must be adopted to reduce development costs and provide a consistent product. Within this study, we investigate microfluidic manufacture of nanomedicines. Using protein-loaded liposomes as a case study, we manufacture liposomes with tightly defined physico-chemical attributes (size, PDI, protein loading and release) from small-scale (1 mL) through to GMP volume production (200 mL/min). To achieve this, we investigate two different laminar flow microfluidic cartridge designs (based on a staggered herringbone design and a novel toroidal mixer design); for the first time we demonstrate the use of a new microfluidic cartridge design which delivers seamless scale-up production from bench-scale (12 mL/min) through GMP production requirements of over 20 L/h using the same standardised normal operating parameters. We also outline the application of tangential flow filtration for down-stream processing and high product yield. This work confirms that defined liposome products can be manufactured rapidly and reproducibly using a scale-independent production process, thereby de-risking the journey from bench to approved product., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Suraj Abraham, Logan Ingalls and Keara Marshall are employees of Precision NanoSystems Inc. Timothy J Leaver is an employee and shareholder of Precision NanoSystems Inc.., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Core-shell nanoparticles (NPs) are attracting increasing interest in nanomedicine as they exhibit unique properties arising from the combined assets of core and shell materials. Porous nanoscale metal-organic frameworks (nanoMOFs) are able to incorporate with high payloads a large variety of drugs. Like other types of NPs, nanoMOFs need to be functionalized with engineered coatings to ensure colloidal stability, control in vivo fate and drug release. To do so, a novel biodegradable cyclodextrin (CD)-based shell was designed in this study. Water soluble γ-CD-citrate oligomers grafted or not with fluorophores were successfully synthesized using citric acid as crosslinker and efficiently anchored onto the surface of porous nanoMOFs. As compared to monomeric CDs, the oligomeric CD coatings could offer higher interaction possibilities with the cores and better possibilities to graft functional moieties such as fluorescent molecules. The amounts of γ-CD-citrate oligomers onto the nanoMOFs were as high as 53 ± 8 wt%. The yield reached up to 86% in the optimized system. These core-shell nanocomposites were stable upon storage, in contrast to the naked nanoMOFs. In addition, the presence of the coating prevented the doxorubicin (DOX)-loaded nanoMOFs from aggregation. Moreover, due to the presence of fluorophores conjugated to the shell, fluorescence-lifetime microscopy enabled deciphering the coating mechanism. DOX loadings reached 48 ± 10 wt% after 24 h incubation with the drug solution. After coating for additional 24 h, DOX loadings reached 65 ± 8 wt%., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Doxorubicin (DOX) is a broad-spectrum anti-tumor drug, but it has certain limitations in its therapeutic effects due to poor tumor selectivity. Chitosan-based pH-sensitive polymers drug delivery systems could improve DOX's activity and selectivity against tumor cells. Understanding the atomic interaction mechanism between chitosan and DOX at different pH levels is important in the design and application of chitosan-based drug delivery systems. In this study, molecular dynamics simulations were performed to investigate the encapsulation and release of DOX by chitosan at different pH levels. Our results show that the protonation state of amine groups of chitosan and the π-π stacking interaction between the conjugated anthraquinone ring of DOX regulate the interaction behavior between chitosan and DOX. Moreover, DOX could gradually release from chitosan at acidic pH environment in tumor tissue. These results revealed the underlying atomic interaction mechanism between DOX and chitosan at various pH levels and may provide novel ideas for the design and application of chitosan-based drug delivery system., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Hypoxia is a characteristic feature of various ischemic diseases, including cancer. This study describes the development of glycol chitosan nanoparticles, hydrophobically modified with 4-nitrobenzyl chloroformate and folic acid (FA), that can specifically release drugs under hypoxic conditions. This hypoxia-responsive glycol chitosan nanoparticle conjugated with FA (HRGF) possesses tumor-targeting properties by virtue of conjugated FA and is able to release drugs in a nitroreductase (NTR)-dependent manner because its structure is cleaved by NTR under hypoxic conditions. HRGF nanoparticles showed improved in vivo cancer-targeting ability compared with HRG nanoparticles without FA. In vitro drug release profiles revealed that doxorubicin (DOX)-loaded HRGF (D@HRGF) nanoparticles showed rapid release under hypoxia conditions than normoxic conditions. In vitro cytotoxicity tests and microscopic observations showed that D@HRGF nanoparticles were more toxic towards hypoxic cells than normoxic cells, and that the release of DOX was more effective in hypoxia than normoxia. In vivo, D@HRGF nanoparticles showed more effective antitumor activity in mice compared with D@HRG and free DOX. Collectively, these results show that HRGF nanoparticles function as an effective drug-delivery system in hypoxic conditions. Moreover, these hypoxia-responsive nanoparticles would be effective not only in cancer, but also in other ischemic diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

A new nanogel/drug carrier of 100-150 nm size, based on poly(N-isopropylacrylamide-co-sodium acrylate) and degradable crosslinker (cystine derivative), was synthesized. Using the electrostatic interactions between the carboxylic groups in the polymer network and the protonated amine groups of doxorubicin it was possible to load the drug into the carrier to a very high level of 28-30% relative to the dry mass of the polymer. The presence of the -S-S- groups made the polymer network susceptible to degradation by glutathione. The size of the nanoparticles was small enough to enable them to easily penetrate the cells. The MTT assay indicated that compared to free doxorubicin the nanogel particles loaded with doxorubicin were more cytotoxic against the MCF-7 and A2780 cancer cells, while they were 150 times less toxic against the MCF-10A healthy cells. The new carrier nanoparticles appeared also to be useful for prolonged drug delivery., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

A facile approach was developed to synthesize an innovative hyaluronic acid-modified carbon dot-doxorubicin nanoparticles drug delivery platform. CD44 targeted HA-modified carbon dots (HA-CDs) were synthesized as carrier by one-step hydrothermal treatment within one hour with citric acid and branch-PEI as core carbon source. HA not only functioned as carbon dot component but also as hydrophilic group and targeting ligand of this system. The as-prepared HA-CDs were then loaded with doxorubicin (HA-CD@p-CBA-DOX) via an acid-cleavable bond, which released drug in a pH-responsive manner. In in vitro experiments, HA-CD@p-CBA-DOX displayed good hemocompatibility and serum stability, while exhibited high cytotoxicity on 4T1 cells. The confocal laser scanning microscopy and flow cytometry results demonstrated that DOX-loaded nanoparticles were internalized by 4T1 cells via HA-mediated CD44-targeting effect. The enhanced in vivo tumor accumulation of HA-CD@p-CBA-DOX was testified by live imaging. Compared with free DOX, superior in vivo anti-tumor efficacy of HA-CD@p-CBA-DOX was observed in both heterotopic and orthotopic 4T1 cell tumor models. Furthermore, blood hematology and blood biochemistry analysis demonstrated that HA-CD@p-CBA-DOX did not induce noticeable toxicity, which further confirmed the good biocompatibility of HA-CD@p-CBA-DOX. The formulated HA-CD@p-CBA-DOX provides an alternative strategy for targeted breast cancer therapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The objective of the current study is to design and delivery of targeted PEG-PCL nanopolymersomes encapsulated with Gadolinium based Quantum Dots (QDs) and Doxorubicin (DOX) as magnetic resonance-florescence imaging and anti-cancer agent. Diagnostic and therapeutic efficiency of the prepared theranostic formulation was evaluated in vitro and in vivo. Hydrophobic QDs based on indium-copper-gadolinium-zinc sulfide were synthesized and characterized extensively. Hydrophobic QDs and hydrophilic DOX were loaded in PEG-PCL polymersomes through double emulsion method. Drug release pattern was studied in both citrate (pH 5.4) and phosphate (pH 7.4) buffer during 10 days. Both fluorescence and magnetic properties of bare QDs and prepared formulations were studied entirely. AS1411 DNA aptamer was covalently attached to the surface of polymersomal formulation in order to prepare targeted drug delivery system. Cellular cytotoxicity and cellular uptake analysis were performed in both nucleolin positive (MCF7 and 4T1) and nucleolin negative (CHO) cell lines. After in vitro evaluations, anti-tumor efficiency and diagnostic capability of the formulation was investigated in 4T1 tumor baring mice. Scanning emission electron microscopy (SEM) confirmed spherical shape and around 100 nm size of prepared formulations. Transmission electron microscopy (HRTEM) showed crystal shape of QDs with size of 2-3 nm. Drug release study obtained controlled release of encapsulated DOX and stability of formulation in physiologic condition. MTT and flow cytometry results demonstrated that AS1411 aptamer could enhance both toxicity and cellular uptake in nucleolin overexpressing cell lines (P < 0.05). Moreover, aptamer targeted formulation could increase survival rate and tumor inhibitory growth effect in 4T1 tumor baring mice (P < 0.05). Our results verify that aptamer targeted polymersomes loaded with non-toxic QDs as a diagnostic agent and DOX as an anti-cancer drug, could provide a theranostic platform with the purpose of optimization of treatment process and minimization of systemic side effects., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Doxorubicin liposomal formulations were characterized for the particle size distribution and size-based distribution of lipids and doxorubicin (DOX). An asymmetric flow-field flow fractionation (AF4) method was developed and employed for size-based fractionation of the doxorubicin liposomal formulations. Liposome size-fractions collected from AF4 were analyzed for particle size using nanoparticle tracking analysis (NTA) and dynamic light scattering (DLS). Three doxorubicin liposomal formulations (DLFs) were compared for liposome size distributions. We did not observe any statistically significant variation in D10, D50 and D90 value of size distributions of three fomulations. Lipids and DOX compositions in liposomal fractions from AF4 were determined using liquid chromatography-mass spectrometry (LC-MS) method. The lipid compositions are close to be constant as a function of liposomal size. The drug to lipid ratio was close to be constant for all the size fractions suggesting drug loading may be proportional to membrane surface area of liposomes as membrane surface area is proportional to the amount of lipid in a given liposome. This analytical method could be used in liposomal based drug development as a tool for comparison of generic versions against the reference standard drug., (Published by Elsevier B.V.)

In a malignant tumor, overexpression of pro-angiogenic factors like vascular endothelial growth factor (VEGF) provokes the production of pathologic vascular networks characterized by leaky, chaotically organized, immature, thin-walled, and ill-perfused. As a result, hostile tumor environment would be developed and profoundly hinders anti-cancer drug activities and fuels tumor progression. In this study, we develop a strategy of sequential sustain release of anti-angiogenic drug, Bevacizumab (BVZ), and anti-cancer drug, Doxorubicin (DOX), using poly (d, l-Lactide)- Poly (ethylene glycol) -Poly (d, l-Lactide) (PDLLA-PEG-PDLLA) hydrogel as a local delivery system. The release profiles of the drugs from the hydrogel were investigated in vitro which confirmed that relatively rapid release of BVZ (73.56 ± 1.39%) followed by Dox (61.21 ± 0.62%) at pH 6.5 for prolonged period. The in vitro cytotoxicity test revealed that the copolymer exhibited negligible cytotoxicity up to 2.5 mg ml -1 concentration on HaCaT and HeLa cells. Likeways, the in vitro degradation of the copolymer showed 41.63 ± 2.62% and 73.25 ± 4.36% weight loss within 6 weeks at pH 7.4 and 6.5, respectively. After a single intratumoral injection of the drug-encapsulated hydrogel on Hela xenograft nude, hydrogel co-loaded with BVZ and Dox displayed the highest tumor suppression efficacy for up to 36 days with no noticeable damage on vital organs. Therefore, localized co-delivery of anti-angiogenic drug and anti-cancer drug by hydrogel system may be a promising approach for enhanced chemotherapeutic efficacy in cancer treatment., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The aim of the present study was to prepare niosome formulations for the simultaneous encapsulation, dual drug therapy, of two anticancer drugs by the ecological probe sonication method. Poloxamer and sorbitan monostearate were used as surface active agents in niosomes, and the water soluble doxorubicin and poorly-water soluble paclitaxel were used as anticancer drugs. Thorough physicochemical analysis were performed for the niosomes, and their cytotoxicity and activity were evaluated on MCF-7 and PC3-MM2 cancer cell lines. Prepared niosomes were small in size with sizes ranging from 137 nm to 893 nm, and entrapment efficiencies were high, ranging from 91.24% to 99.99%. During the four weeks stability testing, the particle size remained stable. The niosomal formulations showed in vitro sustained drug release profiles for doxorubicin and clearly increased the dissolution rate of poorly water soluble paclitaxel. The incorporation of both the drugs into niosomes improved cell penetration and antiproliferative activity of the drugs PC3-MM2 cell lines. As a conclusion, doxorubicin and paclitaxel loaded niosome formulations resulted in relatively stable, small sized niosomes with improved drug release profiles, low toxicity, better cell penetration and antiproliferative activity. The niosomes showed synergistic effect due to the presence of both drugs, which can overcome multidrug resistance., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Brain delivery of drugs by nanoparticles is a promising strategy that could open up new possibilities for the chemotherapy of brain tumors. As demonstrated in previous studies, the loading of doxorubicin in poly(lactide-co-glycolide) nanoparticles coated with poloxamer 188 (Dox-PLGA) enabled the brain delivery of this cytostatic that normally cannot penetrate across the blood-brain barrier in free form. The Dox-PLGA nanoparticles produced a very considerable anti-tumor effect against the intracranial 101.8 glioblastoma in rats, thus representing a promising candidate for the chemotherapy of brain tumors that warrants clinical evaluation. The objective of the present study, therefore, was the optimization of the Dox-PLGA formulation and the development of a pilot scale manufacturing process. Optimization of the preparation procedure involved the alteration of the technological parameters such as replacement of the particle stabilizer PVA 30-70 kDa with a presumably safer low molecular mass PVA 9-10 kDa as well as the modification of the external emulsion medium and the homogenization conditions. The optimized procedure enabled an increase of the encapsulation efficiency from 66% to >90% and reduction of the nanoparticle size from 250 nm to 110 nm thus enabling the sterilization by membrane filtration. The pilot scale process was characterized by an excellent reproducibility with very low inter-batch variations. The in vitro hematotoxicity of the nanoparticles was negligible at therapeutically relevant concentrations. The anti-tumor efficacy of the optimized formulation and the ability of the nanoparticles to penetrate into the intracranial tumor and normal brain tissue were confirmed by in vivo experiments., (Copyright © 2019 Elsevier B.V. All rights reserved.)

We report preparation of theranostic nanocarriers loaded with up to 50 wt% of the anticancer drug doxorubicin that contain magnetic nanoparticles which enable Magnetic Particle Imaging (MPI), an emerging technology for quantitative and unambiguous imaging of the nanocarriers. The nanocarriers, coated with poly(ethylene glycol)-block-poly(lactic acid) (PEG 4.9kD -b-PLA 6kD ) block copolymer for colloidal stability, are composed of a hydrophobic core of precipitated hydrolysable doxorubicin prodrug (proDox) and magnetic nanoparticles. Transmission electron microscopy (TEM) shows evidence of precipitated proDox for nanocarriers with high drug loading of up to 50 wt%. MPI measurements show that the nanocarriers can be quantitatively imaged. The nanocarriers are internalized by MDA-MB-231 cells and their IC 50 value via metabolic assay is 1.1 µM, compared to 0.21 µM for free doxorubicin. The release rate from the nanocarriers was dependent on environmental pH. These nanocarriers with high drug loading and quantitative imaging are promising candidates for future applications., (Copyright © 2019 Elsevier B.V. All rights reserved.)

In this study, polyethylene glycol (PEG) conjugated melanin nanoparticles (MNPs) were prepared (PEG-MNPs). A model chemotherapy drug, doxorubicin (DOX), was loaded into the PEG-MNPs with varied concentrations (0.125, 0.250, 0.500 mg/mL). TEM images showed that, DOX-PEG-MNPs are spherical-shaped and 15 ± 2.2 nm in diameter. FTIR spectroscopy analysis demonstrated that MNPs were successfully modified with PEG. The UV-Vis spectroscopy results showed that the drug loading capacity of MNPs was 0.7 mg/ml of DOX in 2 mg/ml of PEG-MNPs. The time course data showed that, the release behavior of DOX from MNPs was primarily diffusion controlled. In vitro cytotoxicity assays demonstrated that MNP and PEG-MNP did not show any toxic effect on mouse fibroblast cells while DOX-PEG-MNP was able to inhibit the proliferation of human breast cancer cells. The results confirm that the application area of MNPs in controlled and prolonged drug release could be extended to the different types of cancer therapeutics., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Dual-modal imaging probes based on fluorescence (FL) and magnetic resonance (MR) modalities have attracted great attention due to their ability to combine the target specificity and high penetration into body tissues. In this study, we developed a potent nanocarrier with an effective photoluminescent emission and MR imaging capacity to deliver the doxorubicin to breast cancer 4T1 cells. The nanocarrier was fabricated by coating of quantum dots (QDs) with mesoporous silica followed by amine functionalization of the silica surface. Then, the doxorubicin was loaded into the silica pores and biheterofunctional PEG was covalently bound to the surface of core-shell quantum dot mesoporous silica nanoparticles. In order to target the DOX-loaded nanoparticles, the EpCAM DNA aptamer was attached on the surface of the DOX-loaded PEGylated nanoparticles. The synthesized NPs were analyzed for their size distribution, morphology, zeta potential and magnetic susceptibility using HRTEM, SEM and VSM analysis. The QD-encapsulated mesoporous silica revealed spherical shapes with an average particle size of 100 nm. The maximum encapsulation efficacy of doxorubicin in the silica pores was 25%. The in vitro release assessment demonstrated the pH-sensitive release of doxorubicin from the designed formulations. The in vitro cytotoxicity assays indicated that the aptamer targeted nanoparticles showed greater cytotoxicity than both non-targeted NPs and free DOX toward 4T1 and MCF-7 cell lines. The in vivo studies in 4T1 tumor-bearing Balb/c mice demonstrated that EpCAM aptamer could specifically deliver the DOX-loaded nanoparticles into the tumor tissue and cause remarkable inhibition of tumor growth as compared to non-targeted formulation and free DOX. Moreover, the in vivo MR and fluorescent imaging in 4T1 tumor-bearing mice confirmed the accumulation and residence of targeted system in tumor tissue even 24 h post-injection. This work presents a novel system for preparing bimodal imaging theranostic NPs through hybridization of silica and magnetic-fluorescent quantum dots., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Drug carriers with tumor targeting and controlled release have strong prospects for application in safe and efficient chemotherapy. Among various carriers, liposomes have good biocompatibility and can enhance the uptake of drugs by cancer cells. However, traditional liposomes have no specific targeting to cancer cells and are prone to insufficient stability, causing early leakage of the drug. Accordingly, organic-inorganic hybrid phospholipid and thermosensitive phospholipid are deliberately introduced into a liposome system to enhance the morphological and structural stability of the liposomes while realizing thermally controlled drug release. Furthermore, modification with a targeting ligand (WSG-peptide) can endow liposomes with active targeting to ovarian carcinoma cells. First, WSG-peptide was grafted onto the hydrophilic terminal of phospholipid molecules, and the organic-inorganic hybrid cerasome-forming lipid (CFL) was synthesized via a two-step chemical reaction. Then, the WSG-grafted thermosensitive liposomal cerasome (c-LIP-WSG) was prepared by thin-film hydration method. The results showed that the c-LIP-WSG had excellent structural stability both in storage and in a simulated circulation environment. In vitro drug release confirmed that the liposomes exhibited thermally controlled release. Cell uptake experiments and living fluorescence imaging of SKOV-3 tumor-bearing nude mice confirmed that the WSG-peptide modified liposomes were provided with specific targeting properties for ovarian carcinoma., (Copyright © 2019 Elsevier B.V. All rights reserved.)