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The use of nanoparticles as chemotherapeutic carriers has been suggested as a way to overcome a range of side effects associated with classical cancer treatment such as poor selectivity and tumor resurgence. Obtaining precise control of the size and shape of therapeutic nanoparticles is crucial to optimize the targeting of tumor sites. In this work, it is shown that a previously developed system of polypeptide encapsulating individual DNA molecules, that forms rod-shaped nanoparticles of precisely controlled aspect ratio, can be loaded with the DNA-intercalating chemotherapeutic drug doxorubicin (DOX). It is characterized the size and shape of the DOX loaded-Virus-Like DNA Particles (DOX-VLDP) and shown that in this system the DOX payload does not leak out. Through in vitro cell studies, it is shown that DOX-VLDP is internalized by melanoma tumor cells (B16F10 cells) in a delayed and endocytosis-dependent way culminating in increased cytotoxicity and selectivity to tumor cells in comparison with free DOX. In addition, it is found that DOX-VLDP trigger apoptosis and autophagy pathways in treated cells. Taken together, the data on the DOX-VLDP nanoparticles shows that they kill cancer cells differently from free DOX., (© 2023 Wiley-VCH GmbH.)

Chemotherapy is one of the main ways to treat breast cancer clinically. However, the multidrug resistance to anti-tumor drugs limits their clinical use. To overcome these drawbacks, the development of drug delivery systems (DDSs) has attracted more and more attention in cancer therapy. At present, the preparation and purification process are complicated for many reported DDSs, while the clinic calls for new DDSs that are more convenient for preparation. Here a new pH-responsive supramolecular organic framework drug delivery complex loading doxorubicin (DOX) is fabricated. Anti-tumor activity of the system in vitro was investigated by cell cytotoxicity, uptake assay, and cell apoptosis analysis. The anti-tumor activity in vivo was investigated by inspecting nude mice body weight, tumor volume and weight, also a preliminary mechanism probe was conducted by HE and TUNEL staining. The DOX@SOF displayed high stability, good biocompatibility and pH-regulated drug release. At acid condition, the hydrazone bonds would be broken, which result in the dissociation of SOF, and then the drugs would be released from the system. Furthermore, DOX@SOF enhanced cellular internalization. Both in vitro and in vivo experiments reflected that DOX@SOF could enhance the anti-tumor activity of DOX. for the MCF-7/ADR tumor cells and tumors. This study provides a highly efficient strategy to prepare a stimulus-responsive supramolecular drug delivery complex for the treatment of drug-resistant cancer, the results presented inspiring scientific interests in exploring new drug delivery strategies and reversing multi-drug resistance for clinical chemotherapy.

Background: Poor in vivo targeting of tumors by chemotherapeutic drugs reduces their anti-cancer efficacy in the clinic. The discovery of over-expressed components on the tumor cell surface and their specific ligands provide a basis for targeting tumor cells. However, the differences in the expression levels of these receptors on the tumor cell surface limit the clinical application of anti-tumor preparations modified by a single ligand. Meanwhile, toxicity of chemotherapeutic drugs leads to poor tolerance to anti-tumor therapy. The discovery of natural active products antagonizing these toxic side effects offers an avenue for relieving cancer patients' pain during the treatment process. Since the advent of nanotechnology, interventions, such as loading appropriate drug combinations into nano-sized carriers and multiple tumor-targeting functional modifications on the carrier surface to enhance the anti-tumor effect and reduce toxic and side effects, have been widely used for treating tumors., Results: Nanocarriers containing doxorubicin hydrochloride (DOX) and salvianolic acid A (Sal A) are spherical with a diameter of about 18 nm; the encapsulation efficiency of both DOX and salvianolic acid A is greater than 80%. E-[c(RGDfK) 2 ]/folic acid (FA) co-modification enabled nanostructured lipid carriers (NLC) to efficiently target a variety of tumor cells, including 4T1, MDA-MB-231, MCF-7, and A549 cells in vitro. Compared with other preparations (Sal A solution, NLC-Sal A, DOX solution, DOX injection, Sal A/DOX solution, NLC-DOX, NLC-Sal A/DOX, and E-[c(RGDfK) 2 ]/FA-NLC-Sal A/DOX) in this experiment, the prepared E-[c(RGDfK) 2 ]/FA-NLC-Sal A/DOX had the best anti-tumor effect. Compared with the normal saline group, it had the highest tumor volume inhibition rate (90.72%), the highest tumor weight inhibition rate (83.94%), led to the highest proportion of apoptosis among the tumor cells (61.30%) and the lowest fluorescence intensity of proliferation among the tumor cells (0.0083 ± 0.0011). Moreover, E-[c(RGDfK) 2 ]/FA-NLC-Sal A/DOX had a low level of nephrotoxicity, with a low creatinine (Cre) concentration of 52.58 μmoL/L in the blood of mice, and no abnormalities were seen on pathological examination of the isolated kidneys at the end of the study. Sal A can antagonize the nephrotoxic effect of DOX. Free Sal A reduced the Cre concentration of the free DOX group by 61.64%. In NLC groups, Sal A reduced the Cre concentration of the DOX group by 42.47%. The E-[c(RGDfK) 2 ]/FA modification reduced the side effects of the drug on the kidney, and the Cre concentration was reduced by 46.35% compared with the NLC-Sal A/DOX group. These interventions can potentially improve the tolerance of cancer patients to chemotherapy., Conclusion: The E-[c(RGDfK) 2 ]/FA co-modified DOX/Sal A multifunctional nano-drug delivery system has a good therapeutic effect on tumors and low nephrotoxicity and is a promising anti-cancer strategy., (© 2022. The Author(s).)

In the last decade, nanotechnological progress has generated new opportunities to improve the safety and efficacy of conventional anticancer therapies. Compared with other carriers, graphene nanoplatforms possess numerous tunable functionalities for the loading of multiple bioactive compounds, although their biocompatibility is still a debated concern. Recently, we have investigated the modulation of genes involved in cancer-associated canonical pathways induced by graphene engineered with cyclodextrins (GCD). Here, we investigated the GCD impact on cells safety, the HEp-2 responsiveness to Doxorubicin (DOX) and the cancer-related intracellular signalling pathways modulated by over time exposure to DOX loaded on GCD (GCD@DOX). Our studies evidenced that both DOX and GCD@DOX induced p53 and p21 signalling resulting in G 0 /G 1 cell cycle arrest. A genotoxic behaviour of DOX was reported via detection of CDK (T14/Y15) activation and reduction of Wee-1 expression. Similarly, we found a cleavage of PARP by DOX within 72 h of exposure. Conversely, GCD@DOX induced a late cleavage of PARP, which could be indicative of less toxic effect due to controlled release of the drug from the GCD nanocarrier. Finally, the induction of the autophagy process supports the potential recycling of DOX with the consequent limitation of its toxic effects. Together, these findings demonstrate that GCD@DOX is a biocompatible drug delivery system able to evade chemoresistance and doxorubicin toxicity.

In the last decade, nanosized metal organic frameworks (NMOFs) have gained an increasing applicability as multifunctional nanocarriers for drug delivery in cancer therapy. However, only a limited number of platforms have been reported that can serve as an effective targeted drug delivery system (DDSs). Herein, we report rational design and construction of doxorubicin (DOX)-loaded nanoscale Zr (IV)-based NMOF (NH 2 -UiO-66) decorated with active tumor targeting moieties; folic acid (FA), lactobionic acid (LA), glycyrrhetinic acid (GA), and dual ligands of LA and GA, as efficient multifunctional DDSs for hepatocellular carcinoma (HCC) therapy. The success of modification was exhaustively validated by various structural, thermal and microscopic techniques. Biocompatibility studies indicated the safety of pristine NH 2 -UiO-66 against HSF cells whereas DOX-loaded dual-ligated NMOF was found to possess superior cytotoxicity against HepG2 cells which was further confirmed by flow cytometry. Moreover, fluorescence microscopy was used for monitoring cellular uptake in comparison to the non-ligated and mono-ligated NMOF. Additionally, the newly developed dual-ligated NMOF depicted a pH-responsiveness towards the DOX release. These findings open new avenues in designing various NMOF-based DDSs that actively target hepatic cancer to achieve precise therapy., (© 2021. The Author(s).)

Recently, studies showed that the drug-resistant cell membranes have formed high-density lipid rafts regions; traditional targeted drug delivery systems can hardly break through the hard shell and deliver drugs to drug-resistant cells. Here, α-tocopherol polyethylene glycol 2000 succinate (TPGS 2k ) was successfully synthesized and used to modify poly (lactic-glycolic acid) nanoparticles co-loaded with doxorubicin (DOX) and simvastatin (SV) (SV/DOX@TPGS 2k -PLGA NPs). The purpose of this study is to explore the synergistic effect between SV consuming cholesterol in lipid rafts and directly down-regulating P-gp expression on the intracellular drugs retention. The research highlights these nanoparticles interrupted lipid rafts (cholesterol-rich domains, where P-gp is often located), which inhibited drug efflux by down-regulating P-gp, promoted the mitochondria apoptosis and made SW620/AD300 cells (DOX-resistant colon cancer cell line) re-sensitized to DOX. Therefore, the carrier can become a promising SV-based nano-delivery system with depleting cholesterol in lipid rafts to reverse drug resistance., (Copyright © 2020. Published by Elsevier Inc.)

Silica nanoparticles (SiO 2 NPs) synthesized by the Stober method were used as drug delivery vehicles. Doxorubicin hydrochloride (DOX·HCl) is a chemo-drug absorbed onto the SiO 2 NPs surfaces. The DOX·HCl loading onto and release from the SiO 2 NPs was monitored via UV-VIS and fluorescence spectra. Alternatively, the zeta potential was also used to monitor and evaluate the DOX·HCl loading process. The results showed that nearly 98% of DOX·HCl was effectively loaded onto the SiO 2 NPs' surfaces by electrostatic interaction. The pH-dependence of the process wherein DOX·HCl release out of DOX·HCl-SiO 2 NPs was investigated as well. For comparison, both the free DOX·HCl molecules and DOX·HCl-SiO 2 NPs were used as the labels for cultured cancer cells. Confocal laser scanning microscopy images showed that the DOX·HCl-SiO 2 NPs were better delivered to cancer cells which are more acidic than healthy cells. We propose that engineered DOX·HCl-SiO 2 systems are good candidates for drug delivery and clinical applications.

Cancer-based magnetic theranostics has gained significant interest in recent years and can contribute as an influential archetype in the effective treatment of cancer. Owing to their excellent biocompatibility, minute sizes and reactive functional surface groups, magnetic nanoparticles (MNPs) are being explored as potential drug delivery systems. In this study, MgFe 2 O 4 ferrite MNPs were evaluated for their potential to augment the delivery of the anticancer drug doxorubicin (DOX). These MNPs were successfully synthesized by the glycol-thermal method and functionalized with the polymers; chitosan (CHI), polyvinyl alcohol (PVA) and polyethylene glycol (PEG), respectively, as confirmed by Fourier transform infrared (FTIR) spectroscopy. X-ray diffraction (XRD) confirmed the formation of the single-phase cubic spinel structures while vibrating sample magnetometer (VSM) analysis confirmed the superparamagnetic properties of all MNPs. Transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA) revealed small, compact structures with good colloidal stability. CHI-MNPs had the highest DOX encapsulation (84.28%), with the PVA-MNPs recording the lowest encapsulation efficiency (59.49%). The 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT) cytotoxicity assays conducted in the human embryonic kidney (HEK293), colorectal adenocarcinoma (Caco-2), and breast adenocarcinoma (SKBR-3) cell lines showed that all the drug-free polymerized MNPs promoted cell survival, while the DOX loaded MNPs significantly reduced cell viability in a dose-dependent manner. The DOX-CHI-MNPs possessed superior anticancer activity (<40% cell viability), with approximately 85.86% of the drug released after 72 h in a pH-responsive manner. These MNPs have shown good potential in enhancing drug delivery, thus warranting further optimizations and investigations.

Over the years, cyclodextrin uses have been widely reviewed and their proprieties provide a very attractive approach in different biomedical applications. Cyclodextrins, due to their characteristics, are used to transport drugs and have also been studied as molecular chaperones with potential application in protein misfolding diseases. In this study, we designed cyclodextrin polymers containing different contents of β- or γ-cyclodextrin, and a different number of guanidinium positive charges. This allowed exploration of the influence of the charge in delivering a drug and the effect in the protein anti-aggregant ability. The polymers inhibit Amiloid β peptide aggregation; such an ability is modulated by both the type of CyD cavity and the number of charges. We also explored the effect of the new polymers as drug carriers. We tested the Doxorubicin toxicity in different cell lines, A2780, A549, MDA-MB-231 in the presence of the polymers. Data show that the polymers based on γ-cyclodextrin modified the cytotoxicity of doxorubicin in the A2780 cell line.

In the present study, innovative doxorubicin-loaded nanoparticles (NPs) made of a photosensitive poly( o -nitrobenzyl acrylate) (PNBA) hydrophobic matrix and an hydrophilic dextran (Dex) shell were first formulated by the emulsion-solvent evaporation process. Doxorubicin (DOX), a very well-known anticancer drug, was herein chosen as the model. DOX-loaded NPs were successfully produced by covering the hydrophobic PNBA core with Dex chains either physically adsorbed or covalently linked by changing process parameters as the presence of a catalyst (CuBr or CuSO 4 /ascorbic acid). It was then proved that the neutralization of DOX optimized drug loading. DOX loading and release were independent of the coverage mechanism if the catalyst used to covalently link the shell to the core was correctly chosen. Second, the kinetics of DOX release were investigated by simple diffusion or light irradiation of the NPs. Experiments showed that less than 20% of DOX was released by simple diffusion after 48 h in PBS or DMEM media when 45% of DOX released after only 30 s of light irradiation of the NPs. Finally, the impact of the phototriggered DOX release on cell viability was investigated on various cell lines [Caco-2, HepG2, HCT-116, and HT-29 cells as well as murine macrophages (RAW 264.7)]. Cellular mortality was evaluated to be dependent on the cell lines tested. Our approach provided an improved DOX release toward the human liver cancer cell line, and a high internalization of the PNBA-based NPs into HepG2 cells was observed using fluorescence microscopy.

BACKGROUND This study investigated a nanoparticle drug delivery system to reverse multidrug resistance (MDR) and assessed its anticancer efficacy in hepatocellular carcinoma (HCC). MATERIAL AND METHODS Docosahexaenoic acid (DHA) was used as the functional excipient and doxorubicin (DOX) as the chemotherapeutic drug to synthesize DOX nanoparticles (DOX-nano). The human HCC cell line HepG2 was used for experiments. HepG2/DOX, HepG2+DOX, HepG2+DOX-nano, HepG2/DOX+DOX, and HepG2/DOX+DOX-nano groups cells were treated with DOX or DOX-nano (5 μg/mL). Nude mice bearing a HepG2/DOX xenograft were divided into model, DOX, vector-nano, and DOX-nano groups and injected with saline, DOX reagent, vector-nano, and DOX-nano (2 mg/kg), respectively. Next, cytotoxicity, cellular uptake, cell apoptosis and migration, fluorescence imaging, TUNEL assay, and tumor inhibition effects were assessed in vitro and in vivo. Furthermore, expression of MDR-related proteins was also detected using western blotting. RESULTS Fluorescence imaging showed that the DOX uptake in the DOX-nano-treated group was the strongest in the HCC cells or tumors. Cell apoptosis was significantly increased in DOX-nano-treated HepG2/DOX cells and tumors, and cell migration was significantly inhibited in the DOX-nano-treated HepG2/DOX cells compared with the other groups. The tumor inhibitory rate in DOX-nano-injected tumors was also significantly higher than in other groups. The expression of breast cancer resistance protein, B-cell lymphoma 2, lung resistance protein, multidrug resistance protein, and protein kinase C alpha was significantly decreased in DOX-nano-treated HepG2/DOX cells and xenograft tumors. Significantly better antitumor and MDR-reversing effects were also observed in the HepG2+DOX group compared with the HepG2/DOX group. CONCLUSIONS This study revealed the potential efficacy of a DOX-nano drug delivery system for the treatment of HCC, using HepG2/DOX cells and nude mice bearing HepG2/DOX xenografts.

The combination therapy which has been proposed as the strategy for the cancer treatment could achieve a synergistic effect for cancer therapies and reduce the dosage of the applied drugs. On account of the the unique properties as the high absorbed water content, biocompatibility, and flexibility, the targeting nanogels have been considred as a suitable platform. Herein, a non-toxic pH/thermo-responsive hydrogel P(NIPAAm-co-DMAEMA) was synthesized and characterized through the free-radical polymerization and expanded upon an easy process for the preparation of the smart responsive nanogels; that is, the nanogels were used for the efficient and controlled delivery of the anti-cancer drug doxorubicin (DOX) and chemosensitizer curcumin (CUR) simultaneously like a promising strategy for the cancer treatment. The size of the nanogels, which were made, was about 70 nm which is relatively optimal for the enhanced permeability and retention (EPR) effects. The DOX and CUR co-loaded nanocarriers were prepared by the high encapsulation efficiency (EE). It is important to mention that the controlled drug release behavior of the nanocarriers was also investigated. An enhanced ability of DOX and CUR-loaded nanoformulation to induce the cell apoptosis in the HT-29 colon cancer cells which represented the greater antitumor efficacy than the single-drug formulations or free drugs was resulted through the In vitro cytotoxicity. Overall, according to the data, the simultaneous delivery of the dual drugs through the fabricated nanogels could synergistically potentiate the antitumor effects on the colon cancer (CC).

This study aimed to develop biodegradable calcium alginate microcarriers with uniform particle size and spherical integrity for sustained-release targeting transarterial chemoembolization. To determine related parameters including the ratio of cross-linking volume (sodium alginate: CaCl 2 ), concentrations of sodium alginate and CaCl 2 solutions, collection distance, flow rate, stirring speed, syringe needle diameter and hardening time to fabricate the microcarriers, the Taguchi method was applied. Using different conditions, a total of 18 groups were prepared. The average size of microspheres from different groups was estimated as ~ 2 mm (range 1.1 to 1.6 mm). Signal-to-noise ratio analysis showed the optimal spherical integrity (F1) achieved when the above parameters were designed as 0.1, 2.5 wt%, 6 wt%, 8 cm, 30 mL/h, 150 rpm, 0.25 mm and 2 h, respectively. The best (F1), middle (F2) and worst (F3) groups were used for further experiments. Fourier-transform infrared spectroscopy spectrum showed that F1, F2 and F3 conformations were distinct from original sodium alginate. Drug-loaded calcium alginate microcarriers demonstrated rougher surfaces compared to microspheres without drug under transmission electron microscopy. Compared to pH 7.4, swelling rates in PBS were decreased at pH 6.5. Encapsulation and loaded efficiencies of the Dox-loaded microcarriers were estimated as ~ 40.617% and ~ 3.517%. In vitro experiments indicated that the F1 Dox-loaded microcarriers provide a well sustained-release efficacy for about two weeks at 37 °C in PBS. Treatments of calcium alginate microcarriers without the Dox in two distinct hepatocellular carcinoma-derived cell lines, Huh-7 and Hep-3B, indicated that these microcarriers were non-toxic. The Dox-loaded microcarriers displayed sustained-release capacity and reduced cell viabilities to ~ 30% in both cell lines on Day 12.

Contrast-enhanced ultrasound (CEUS) is widely applied in cancer diagnosis clinically. However, the gas-filled contrast agents are unstable in the blood and exhibit shorter imaging time, which limit their clinical use. In this study, a diagnostic nanoparticle system was developed for dual-mode imaging (ultrasound and fluorescence), which after encapsulation with doxorubicin (DOX) demonstrated simultaneous therapeutic function towards cancer treatment. Thus, calcium carbonate (CaCO 3 ) nanoparticles were encapsulated with doxorubicin (DOX) to obtain CaCO 3 -DOX. Under acidic conditions, it produced carbon dioxide (CO 2 ) to enhance ultrasound imaging and increase the release of DOX. After intravenously injecting CaCO 3 -DOX to tumor-bearing mice, in the presence of an ultrasound field, CO 2 bubbles were sufficiently generated at the tumor tissues for echogenic reflectivity. Also, the indocyanine green (ICG) was encapsulated into CaCO 3 nanoparticles, to further detect the tumor with fluorescence. The resultant theranostic nanoparticle system exhibited therapeutic efficacy towards tumour-bearing mice. Overall, this investigation provides an attractive strategy for dual-mode cancer diagnostics., 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.)

This study aimed to develop new organic/inorganic nanohybrids of targeted pullulan derivative/gold nanoparticles (FA-PABA-Q188-PUL@AuNPs) to improve the selectivity and efficacy of drugs. The chemical structure of targeted pullulan derivative, folic acid-decorated para-aminobenzoic acid-quat188-pullulan (FA-PABA-Q188-PUL), was designed for reducing, stabilizing, capping, and functionalizing AuNPs. Here, the key factors, including pH, temperature, and FA-PABA-Q188-PUL concentrations, were systematically optimized to control the morphology, size, and functionalization of multifunctional FA-PABA-Q188-PUL@AuNPs. Spherical FA-PABA-Q188-PUL@AuNPs obtained by a green, simple, and bio-inspired strategy under the optimum conditions were thoroughly characterized and had an average size of 12.6 ± 1.5 nm. The anticancer drug DOX was successfully loaded on monodispersed FA-PABA-Q188-PUL@AuNPs and the system exhibited excellent intracellular uptake, specificity, and physicochemical properties. The pH-responsive DOX release from FA-PABA-Q188-PUL@AuNPs-DOX showed fast release (85% after 72 h) under acidic conditions. Furthermore, FA-PABA-Q188-PUL@AuNPs-DOX enhanced the anticancer activity of DOX toward Chago-k1 cancer cells up to 4.8-fold and showed less cytotoxicity toward normal cells than free DOX. The FA-PABA-Q188-PUL@AuNPs-DOX induced the death of cells by increasing late apoptotic cells (26.4%) and arresting the cell cycle at S-G2/M phases. These results showed that innovative FA-PABA-Q188-PUL@AuNPs should be considered as new candidate platforms for anticancer drug delivery systems., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Dual drug-loaded nanotherapeutics can play an important role against the drug resistance and side effects of the single drugs. Doxorubicin and sorafenib were efficiently co-encapsulated by tailor-made poly([R,S]-3-hydroxybutyrate) (PHB) using an emulsion-solvent evaporation method. Subsequent poly(ethylene glycol) (PEG) conjugation onto nanoparticles was applied to make the nanocarriers stealth and to improve their drug release characteristics. Monodisperse PHB-sorafenib-doxorubicin nanoparticles had an average size of 199.3 nm, which was increased to 250.5 nm after PEGylation. The nanoparticle yield and encapsulation efficiencies of drugs decreased slightly in consequence of PEG conjugation. The drug release of the doxorubicin was beneficial, since it was liberated faster in a tumor-specific acidic environment than in blood plasma. The PEG attachment decelerated the release of both the doxorubicin and the sorafenib, however, the release of the latter drug remained still significantly faster with increased initial burst compared to doxorubicin. Nevertheless, the PEG-PHB copolymer showed more beneficial drug release kinetics in vitro in comparison with our recently developed PEGylated poly(lactic-co-glycolic acid) nanoparticles loaded with the same drugs.

The in vitro and in vivo handling and performance characteristics of a small caliber radiopaque embolic microsphere, 40-90 μm DC Bead LUMI™ (LUMI40-90), were studied. Microsphere drug loading and elution and effects on size, suspension, and microcatheter delivery were evaluated using established in vitro methodologies. In vivo evaluations of vascular penetration (rabbit renal artery embolization), long-term biocompatibility and X-ray imaging properties, pharmacokinetics and local tissue effects of both doxorubicin (Dox) and irinotecan (Iri) loaded microspheres (swine hepatic artery embolization) were conducted. Compared to 70-150 μm DC Bead LUMI (LUMI70-150), LUMI40-90 averaged 70 μm versus 100 μm, which was unchanged upon drug loading. Handling, suspension, and microsphere delivery studies were successfully performed. Dox loading was faster (20 min) and Iri equivalent (<10 min) while drug elution rates were similar. Contrast suspension times were longer with no delivery complications. Vascular penetration was statistically greater (rabbit) with no unexpected adverse safety findings (swine). Microspheres ± drug were visible under X-ray imaging (CT) at 90 days. Peak plasma drug levels and area under the curve were greater for LUMI40-90 compared to LUMI70-150 but comparable to 70-150 μm DC BeadM1™ (DC70-150). Local tissue effects showed extensive hepatic necrosis for Dox, whereas Iri displayed lower toxicity with more pronounced lobar fibrosis. LUMI40-90 remains suspended for longer and have greater vessel penetration compared to the other DC Bead LUMI sizes and are similarly highly biocompatible with long-term visibility under X-ray imaging. Drug loading is equivalent or faster with pharmacokinetics similar to DC70-150 for both Dox and Iri., (© 2020 The Authors. Journal of Biomedical Materials Research Part B: Applied Biomaterials published by Wiley Periodicals LLC.)

The multidrug resistance (MDR) which widely observed in multiple cancer types is responsible for the poor chemotherapy benefits of doxorubicin (Dox). Here in our study, Dox was firstly loaded into a scramble siRNA and then condensed by polyethyleneimine (PEI) 25k together with anti-autophagy siRNA, the obtained PEI/Si-D containing mirror RNAs was further coated with hyaluronic acid (HA) to shield the surface charge of PEI and offer tumor-homing property that finally developed a platform for effective cancer chemotherapy (HP/Si-D). Our results revealed that the obtained HP/Si-D was showed high stability and biocompatibility with promising transfection profile. As a result, the anti-autophagy siRNA downregulated autophagy level of target cells, which further decreased ATP supply to enhance drug retention and cell cycle arrest. These results contributed significantly to reverse the MDR of A549/Dox (Dox resistance A549 cell line) cells with promising in vitro and in vivo results, which suggested the potential of effective MDR cancer therapy using synergistic anti-autophagy and chemotherapy., (Copyright © 2020. Published by Elsevier Masson SAS.)

How to overcome the cell membrane barriers and achieve release payloads efficiently in the cytoplasm have been major challenges for anticancer drug delivery and therapeutic effects with nanosystems. In this study, bovine serum albumin (BSA) was modified with folate acid and histamine, which was then used as the nanocarrier for the antitumor agent doxorubicin (DOX). The DOX-loaded nanoparticles (DOX/FBH-NPs) were prepared via a crosslinking method, and the release of DOX from these nanoparticles (NPs) exhibited pH/reduction-responsive behaviors in vitro. These NPs interacted with the folate receptor overexpressed on the cell membrane of 4 T1 cells and achieved enhanced endocytosis. Afterwards, these NPs exhibited pH-responsiveness within endo-lysosomes and escaped from endosomes due to the "proton sponge" effect, and then completed release of DOX was triggered by high concentration of glutathione (GSH) in cytoplasm. Thus, DOX/FBH-NPs exhibited excellent cytotoxicity against 4 T1 cells in vitro. Benefited from the enhanced permeability and retention (EPR) effect and folate receptor-mediated endocytosis, these NPs gained satisfied tumor-targeting effects in vivo and efficient delivery of DOX to tumor tissues. As a result, these NPs exhibited enhanced antitumor effects and reduced side effects in vivo. In conclusion, these BSA-based NPs modified with both folate acid and histamine showed enhanced tumor-targeting effects in vivo with good biocompatibility and intracellular pH/reduction-responsive behaviors, providing a promising strategy for the efficient delivery of antitumor agents., 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.)

Induction of apoptosis in tumor cells specifically within the complex tumor microenvironment is highly desirable to kill them efficiently and to enhance the effects of chemotherapy. Second mitochondria-derived activator of caspase (Smac) is a key pro-apoptotic pathway which can be activated with a Smac mimetic peptide. However, in vivo application of peptides is hampered by several limitations such as poor pharmacokinetics, rapid elimination, enzymatic degradation, and insufficient intracellular delivery. In this study, we developed a nanosystem to deliver a Smac peptide to tumor by passive targeting. We first synthesized a chimeric peptide that consists of the 8-mer Smac peptide and a 14-mer cell penetrating peptide (CPP) and then encapsulated the Smac-CPP into polymeric nanoparticles (Smac-CPP-NPs). In vitro, Smac-CPP-NPs were rapidly internalized by 4T1 mammary tumor cells and subsequently released Smac-CPP into the cells, as shown with fluorescence microscopy. Furthermore, Smac-CPP-NPs induced apoptosis in tumor cells, as confirmed with cell viability and caspase 3/7 assays. Interestingly, combination of Smac-CPP-NPs with doxorubicin (dox), a clinically used cytostatic drug, showed combined effects in vitro in 4T1 cells. The effect was significantly better than that of SMAC-CPP-NPs alone as well as empty nanoparticles and dox. In vivo, co-treatment with Smac-CPP-NPs and free dox reduced the tumor growth to 85%. Furthermore, the combination of Smac-CPP-NPs and free dox showed reduced proliferating tumor cells (Ki-67 staining) and increased apoptotic cells (cleaved caspase-3 staining) in tumors. In conclusion, the present study demonstrates that the intracellular delivery of Smac-mimetic peptide using nanoparticle system can be an interesting strategy to attenuate the tumor growth and to potentiate the therapeutic efficacy of chemotherapy in vivo., 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.)

Combination of chemotherapy and immunotherapy has been a promising strategy in cancer treatment. Polysaccharides from Angelica sinensis (AP), a well-known Chinese herbal medicine, have been proved to have good immunomodulatory activity. In the present study, an enzyme-sensitive tumor-targeting nano drug delivery system (AP-PP-DOX (doxorubicin), PP stood for peptide) was constructed. In this system, Angelica polysaccharides act as not only carriers to targeted delivery of drugs to tumor tissue but also effectors to improve tumor microenvironment and enhance immune function, resulting in synergistic antitumor effect with chemotherapy drugs. The structure of this conjugate was confirmed by FI-IR and 1 H-NMR. The particle size and zeta potential of the nanoparticles were 129.00 ± 3.32 nm and -28.45 ± 0.22 mV, respectively. Doxorubicin (DOX) and AP could be quickly released from the AP-PP-DOX under the presence of matrix metalloproteinase 2 (MMP2). The released DOX showed good antitumor efficacy in vitro . The treatment of released AP moiety increased the expression of IL-2, while that of IL-10 was decreased, showing potential in restoring Th1/Th2 immune balance in tumor microenvironment. In a word, this drug delivery system, with specific tissue targeting and tumor microenvironment improvement, will open a new avenue for combination treatment of cancer.

Multifunctional nanocarriers have been widely accepted and utilized for biomedical applications, because of their structural regularity, convenient post-modification and controllable structure and morphology. Herein, we reported polydopamine-doped virus-like mesoporous silica coated reduced graphene oxide nanosheets (rGO@PVMSNs) nanocomposites by a facile oil-water biphase stratification method. The synthesized rGO@PVMSNs nanocomposites performed excellent biocompatibility and photothermal performance. They could be employed as photoacoustic imaging contrast in vivo. Furthermore, the rGO@PVMSNs nanocarriers were used for loading the antitumor drug doxorubicin (DOX), the rGO@PVMSNs@DOX nanocomposites were also demonstrated to be with high inhibition of HepG2 cancer cells, especially with the help of near-infrared irradiation, which were more efficient than single chemotherapy or photothermal therapy. The rGO@PVMSNs@DOX nanocomposites of this work could be used as photoacoustic imaging and chemo-photothermal synergetic therapy agents, which show a new perspective for clinical tumor diagnosis and therapy.

To promote the targeted cancer therapy, the pH-sensitive small molecule nanodrug self-assembled from amphiphilic vitamin B6-E analogue conjugate was successfully constructed. Herein, water-soluble vitamin B6 with pKa (5.6) was chemically conjugated to lipid-soluble vitamin E succinate (α-TOS), which showed selective cancer cell killing ability and this amphiphilic small molecule vitamin conjugate could self-assemble to be free nanoparticles (NPs) and doxorubicin-loaded NPs (α-TOS-B6-NPs-DOX). The small molecule nanodrugs could perform the following characteristic: (i) stability in the sodium dodecyl sulfonate (SDS) solution and long-term storage stability in PBS via surface negative charge; (ii) tumor accumulation by enhanced penetration and retention (EPR) effect; (iii) improved cellular internalization by means of vitamin B6 transporting membrane carrier (VTC); and (iv) facilitating endosomal escape and rapid drug release for synergistic toxicity to tumor cells via charge reversal and ester hydrolysis at intracellular pH and/or esterase. Moreover, α-TOS-B6-NPs-DOX exhibited long blood circulation stability and significant tumor accumulation and inhibition with the decreased side effects in vivo. Thus, the pH-sensitive small molecule nanodrug self-assembled from amphiphilic vitamin B6-E analogue conjugate could be the potential drug carriers in targeted synergistic cancer therapy., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

We report benzeneselenol-modified gold nanoclusters (Se&#95;Au NCs) that have significant anticancer activity by inducing autophagy and disassembly of F-actin in cancer cells. Upon treatment of different tumor models on mice, it has been found that Se&#95;Au NCs exhibit excellent antitumor efficacy, high stability, and extremely low toxicity, which are the requirements for an ideal antineoplastic drug. Our study is a successful attempt in exploring novel anticancer agents with high biosafety.

In this study, an adjustable pH-responsive drug delivery system using mesoporous silica nanoparticles (MSNs) as the host materials and the modified polypeptides as the nanovalves is reported. Since the polypeptide can self-assemble via electrostatic interaction at pH 7.4 and be disassembled by pH changes, the modified poly(l-lysine) and poly(l-glutamate) are utilized for pore blocking and opening in the study. Poly(l-lysine)-MSN (PLL-MSN) and poly(l-glutamate)-MSN (PLG-MSN) are synthesized via the ring opening polymerization of N-carboxyanhydrides onto the surface of mesoporous silica nanoparticles. The successful modification of the polypeptide on MSN is proved by Zeta potential change, X-ray photoelectron spectroscopy (XPS), solid state NMR, and MALDI-TOF MS. In vitro simulated dye release studies show that PLL-MSN and PLG-MSN can successfully load the dye molecules. The release study shows that the controlled release can be constructed at different pH by adjusting the ratio of PLL-MSN to PLG-MSN. Cellular uptake study indicates that the drug is detected in both cytoplasm and nucleus, especially in the nucleus. In vitro cytotoxicity assay indicates that DOX loaded mixture nanoparticles (ratio of PLL-MSN to PLG-MSN is 1:1) can be triggered for drug release in HeLa cells, resulting in 88% of cell killing., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

To extend the applications of natural products in nanomedicine, novel cellulose-based supramolecular nanoparticles (SNPs) were fabricated via a host-guest driven self-assembly strategy here. The adamantane-grafted carboxyethyl hydroxyethyl cellulose and β-cyclodextrin-grafted glycerol ethoxylate were synthesized to self-assemble into the SNPs. Furthermore, doxorubicin (DOX)-functionalized β-cyclodextrin was encapsulated into SNPs via an in situ co-assembly process to generate DOX-loaded SNPs (DOX-SNPs). The SNPs exhibited a quasi-spherical morphology with an average diameter of ∼25 nm. The DOX-SNPs with relatively larger diameter possessed a high DOX loading efficiency (∼94 %) and the pH-responsive drug release behaviors, which made them suitable as a drug delivery system. In vitro cytotoxicity assays demonstrated the excellent cytocompatibility of SNPs and the efficient inhibition of Hela cell proliferation of DOX-SNPs. Moreover, the DOX-SNPs could effectively enter Hela cells via endocytosis and release DOX under endo/lysosome pH. Thus, this nanocarrier has promising translational potential in cancer therapy and personalized nanomedicine., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Crystallographically characterized M 2 L 4 type cationic Cu(II)-metallacryptands [MC(X)] derived from a series of bis-pyridyl-bis-urea ligands (L X ; X = O, S, C) are self-assembled to single-layered vesicular aggregates in DMSO, DMSO/water, and DMSO/DMEM (biological media). One such vesicle is MC(O)-vesicle that is demonstrated to be able to load and release (pH responsive) an anticancer drug, namely doxorubicin hydrochloride (DOX). DOX-loaded MC(O)-vesicle is also successfully transported within MDA-MB-231 cells-a highly aggressive human breast cancer cell line. Such self-assembling behavior to form vesicular aggregates by metallacryptands (MCs) is hitherto unknown., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

(1) Background: doxorubicin is a potent chemotherapeutic agent, but it has limitations regarding its side effects and therapy resistance. Hydrogels potentially deal with these problems, but several characterizations need to be optimized to better understand how hydrogel assisted chemotherapy works. Poloxamer 407 (P407) hydrogels were mixed with doxorubicin and physico-chemical, biological, and pharmacological characterizations were considered. (2) Methods: hydrogels were prepared by mixing P407 in PBS at 4 °C. Doxorubicin was added upon solutions became clear. Time-to-gelation, hydrogel morphology, and micelles were studied first. The effects of P407-doxorubicin were evaluated on MC-38 colon cancer cells. Furthermore, doxorubicin release was assessed and contrasted with non-invasive in vivo whole body fluorescence imaging. (3) Results: 25% P407 had favorable gelation properties with pore sizes of 30-180 µm. P407 micelles were approximately 5 nm in size. Doxorubicin was fully released in vitro from 25% P407 hydrogel within 120 h. Furthermore, P407 micelles strongly enhanced the anti-neoplastic effects of doxorubicin on MC-38 cells. In vivo fluorescence imaging revealed that hydrogels retained fluorescence signals at the injection site for 168 h. (4) Conclusions: non-invasive imaging showed how P407 gels retained drug at the injection site. Doxorubicin P407 micelles strongly enhanced the anti-tumor effects., Competing Interests: C.K.C. is on the payroll of JeNaCell GmbH and studying for a PhD at LUMC in a joint industrial-academic partnership sponsored by the European Commission (Project: ISPIC - MSCA-ITN-ETN Proposal Number: 675743). A.C. is a founder of Percuros B.V. and is also coordinator of the project: MSCA-ITN-ETN Proposal Number: 675743. D.K. is a founder of JeNaCell GmbH and a co-supervisor of the PhD study being undertaken by C.K.C.

Carbon quantum dots (Cdots) have attracted more and more interests in bioimaging and tumor theranostics. However, their practical application has been limited due to the small particle size and non-tumor-specific fluorescence. Here, reduction-cleavable disulfide-linked Cdots-based nanoclusters were fabricated to conjugate doxorubicin (DOX) via an acid-labile hydrazone bond. Owing to the pH and reduction dual-stimuli responsiveness, the proposed Cdots-based nanotheranostics possessed unique tumor-specific fluorescent property and tumor-specific controlled drug release performance, indicating their promising potential for the in-situ real-time fluorescent monitoring of therapeutic response in future tumor therapy., Competing Interests: Declaration of competing interest There are no conflicts to declare., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Amphiphilic polystyrene-b-poly[(7-(Allyloxy)-2H-chromen-2-one)-co-(2-hydroxyethyl methacrylate)]-b-poly(2-(dimethylamino)ethyl methacrylate) (PS-b-P(AC-co-HEMA)-b-P(DMAEMA)) triblock terpolymers were synthesized by atom transfer radical polymerization (ATRP). PS-b-P(AC-co-HEMA)-b-PDMAEMA triblock terpolymers were characterized using proton nuclear magnetic resonance ( 1 H NMR) and gel permeation chromatography (GPC). The effect of various pH values on solution self-assembly behavior of PS-b-P(AC-co-HEMA)-b-P(DMAEMA) triblock terpolymers was investigated. Field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), fluorescence microscopy, and dynamic light scattering (DLS) were used to observe the size and morphology of the assembled triblock terpolymers. With altering pH value, different morphologies were obtained including spherical micelles, Janus snowman, and spherical Janus as well as cubic-hexagonal structures. UV light was used to stabilize the self-assembled morphologies and FE-SEM results showed that morphology remained unchanged after photo-dimerization. The self-assembled triblock terpolymers before and after photo-crosslinking were loaded with doxorubicin (DOX) and drug release behavior was examined at different conditions. Due to photo-crosslinking of self-assembled terpolymers, cumulative release was decreased. Thus, they might be more controllable drug carriers in drug delivery systems., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

A novel nanocarrier based-on hollow mesoporous carbon nanospheres (HMCNs) with primary amines on its surface, a large cavity, and good hydrophilicity was synthesized by a hydrothermal reaction. The primary amine functionalities on the mesoporous carbon were used as the initiation sites for growing poly (epichlorohydrin) (PCH) chains. The chlorine groups in the side chain of PCH were replaced with imidazole as the pendant groups. Calcium chloride (CaCl 2 ) was applied as a capping agent. The coordination bonding was formed between pendant imidazole groups and calcium ions. Doxorubicin (DOX) was selected as a model of hydrophilic anticancer drug and was loaded onto the nanocarrier and released through the cleavage of the pH-sensitive coordination bonding. The gating mechanism enables the nanocarrier to store and release the calcium ions and the DOX molecules trapped in the pores. MTT assay toward HeLa cells indicated that the nanocarrier had low toxicity because of the surface modification with the oxygen-rich polymer. The cellular uptake of the pH-sensitive nanocarrier for HeLa cancer cell lines was confirmed by CLSM images and flow cytometry. So, the novel pH-sensitive nanocarrier can be applicable to carry and release both DOX drug and calcium ions for cancer treatment., Competing Interests: Declaration of competing interest None., (Copyright © 2019. Published by Elsevier B.V.)

Giving patients right dosage is an essential concept of precision medicine. Most of nanocarriers lack of flexible drug capacity and structural stability to be customized for specific treatment, resulting in low therapeutic efficacy and unexpected side effects. Thus, a growing need emerges for fast and rigorous approaches to develop nanoparticles with properties of adjustable dosage and controllable particle size. Poly-l-Lysine is known for its enhanced bioadhesivity and pH-triggered structural swelling effect, which is utilized as the main agent to activate the multistage drug releasing. Inspired by natural bio-assembly system, we report a simple method to self-assemble Poly-l-Lysine-based nanoparticles via supramolecular recognitions of cross-linked pyrenes, which provides noncovalent force to flexibly encapsulate Doxorubincin and to construct robust nanostructures. Pyrene-modified polypeptide self-assemblies are able to adjust drug payload from 1: 10 to 2:1 (drug: polypeptide) without changing its uniform nano-spherical morphology. This nanostructure remained the as-made morphology even after experiencing the long-term (~ 10 weeks) storage at room temperature. Also, the nanoparticles displayed multi-step drug release behaviours and exhibited great in vitro and in vivo cytotoxicity towards colon cancer cells. The as-mentioned nanoparticles provide a novel perspective to compensate the clinical needs of specific drug feedings and scalable synthesis with advantages of simple-synthesis, size-adaptivity, and morphology reversibility., 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.)

In response to extreme environmental conditions, Bactrian camels with largest population in China have evolved with the unique and extraordinary stress-tolerant mechanism in the bodies, in which the most abundantly secreted serum albumins contribute to an important role in diverse physiological activities such as maintaining osmotic pressure and transporting endogenous/exogenous molecules. In this study, we have for the first time purified Chinese Bactrian camel serum albumins (CSA) aimed at exploring their biomedical application. The mass spectrometric as well as structural analysis of CSA have revealed the sequence consensus and alpha-helix abundant structures among its heterologous proteins. Using desolvation methods, CSA-based nanoparticles have been prepared to encapsulate two substrate molecules including Doxorubicin (Dox) and hemin, which confers the versatility of nanocomposite. As drug delivery matrix, the Dox-loaded CSA nanoparticles displayed sustained release behaviors of DOX with the decreased cytotoxicity detected by both CCK-8 assay and real-time cell analysis. The CSA-hemin nanoparticles exhibited superior catalytic activities in the oxidation of Orange II comparable with horse radish peroxidase following a ping-pong mechanism. Furthermore, the constructed CSA-hemin nanoparticles were applied for the spectroscopic detection of H 2 O 2 resulting in a wide linear calibration curve ranging from 5 to 400 μM with a detection limit of 3.32 μM., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The optimal drug delivery system should be biocompatible, biodegradable, and allow the sustained release of the drug only after it reaches the target cells. Silk, as a natural polymer, is a great candidate for building drug carriers. Genetically engineered silks offer the possibility of functionalization. Previously, we characterized bioengineered silk spheres that were functionalized with H2.1 peptide that selectively delivered a drug to Her2-positive cancer cells. However, drug leakage from the silk spheres showed the need for improved control., Results: To control the drug loading and release, we designed and produced functional silk (DOXMS2) that contains a DOX peptide with an affinity for doxorubicin. The DOXMS2 spheres showed the decreased release of doxorubicin compared with MS2 particles. Next, the DOXMS2 silk was blended with the H2.1MS1 polymer to improve the control of doxorubicin binding and release into Her2-positive cancer cells. The H2.1MS1:DOXMS2 particles showed the highest doxorubicin-loading capacity and binding per cell, which resulted in the highest cytotoxic effect compared with that of other sphere variants. Since drug release at a pH of 7.4 from the blended H2.1MS1:DOXMS2 particles was significantly lower than from blended spheres without DOXMS2 silk, this indicated that such particles could control the release of the drug into the circulatory system before the carrier reached the tumor site., Conclusions: This strategy, which is based on the blending of silks, allows for the generation of particles that deliver drugs in a controlled manner.

Large-scale preparation of biocompatible drug delivery systems with targeted recognition and controlled release properties has always been attractive. However, this strategy has been constrained by a lot of design challenges, such as complicated steps and premature drug release. Herein, in this paper, we address these problems by a facile in situ mineralization method, which synthesizes biodegradable tea polyphenol coated monodisperse calcium phosphate nanospheres using for targeted and controlled delivery of doxorubicin. Dialysis diffusion method was used to control ion release to form mineralized nanospheres. The polyphenol coatings and calcium phosphate used in this work could be biodegraded by intracellular glutathione and acidic microenvironment, respectively, resulting the release of encapsulated drug. According to confocal fluorescence microscopy, and cytotoxicity experiments, the prepared tea polyphenol functionalized, doxorubicin loaded calcium phosphate nanospheres were confirmed to have highly efficient internalization and obvious cell killing effect on target tumor cells, but not normal cells. Our results suggest that these tea polyphenols functionalized calcium phosphate nanospheres are promising vehicles for controlled release of an anticancer drug in cancer therapy.

Metal-organic frameworks (MOFs) formed by coordination between metal ions or clusters and organic bridging ligands possess great potential for biomedicine applications, given their high biocompatibility and biodegradability. Compared with the traditional three-dimensional (3D) MOFs, two-dimensional (2D) MOFs with sheet-like morphologies exhibit unique properties. In this study, a nanoscale 2D leaf-shaped MOF (NZIF-L) was synthesized via coordination self-assembly between 2-methylimidazole (Hmim) and Zn 2+ with subsequent morphology and size control. The fabricated NZIF-L is cytocompatible and can be quickly endocytosed, which makes it an excellent cargo carrier. Subsequent to loading with either doxorubicin (DOX) or 4,4'-(1,2-diphenylvinyl)-1,2-di-(phenylcarboxylic acid) (TCPE), the respectively obtained DOX@NZIF-L and TCPE@NZIF-L showed promise for killing and imaging cancer cells., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

In this work, a new pH-responsive nanohybrid carrier was prepared with chelating ZnO-dopamine (Zn-d) on the surface of graphene oxide. Doxorubicin (DOX) as a model drug was loaded on the resulted nanohybrid. The characteristics of Zn-d-rGO nanohybrid (NH) determined using Fourier transformed infrared spectroscopy (FT-IR), X-ray Diffraction spectroscopy (XRD), UV-Visible spectroscopy, Scanning Electron Microscope (SEM), EDX and AFM. The BET analysis showed a specific surface area of 37.16 m 2 /g and the obtained nanohybrid indicated a high loading capacity of DOX up to 99.7%, and the release profile displayed a pH-dependent discharge in the acidic environment for14 days. The cytotoxicity of the prepared nanohybrid was measured against T47D and MCF10A cells and it confirmed that as-prepared nanohybrid has high toxicity against cancer cells and lower effect against human breast cell. Meanwhile, the prepared nanohybrids showed well antimicrobial activity against gram-positive and negative bacteria. The obtained results showed that the prepared nanohybrid (Zn-d-rGO) could potentially be used as a safe carrier for drug delivery systems., (Copyright © 2019 Elsevier B.V. All rights reserved.)

A novel bio-responsive co-delivery system based on Poly(DEA)-b-Poly(ABMA-co-OEGMA) (PDPAO, prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization) copolymers was constructed for enhanced cellular internalization and effective combination therapy. Reduction-sensitive 6-mercaptopurine (6MP) based prodrug and pH-sensitive doxorubicin (DOX) based prodrug were grafted onto PDPAO by an azide-alkyne "Click Chemistry" reaction to acquire a pH/reduction-sensitive polymeric prodrug (PDPAO@imine-DOX/cis-6MP), which was able to self-aggregate to form polymeric micelles (M(DOX/6MP)) with an average particle size of 116 ± 2 nm in the water. The resultant micelles could maintain a stable sphere structure and show stability with a small particles' dispersion index in the blood. Importantly, it has been observed that the pH-sensitive surface charge-conversion accompanied pH-triggered DOX release in the biomimetic extracellular acidic environment of tumor tissue and a rapid dual-drug release triggered by pH and GSH in the intracellular environment. The in vitro evaluation of micelles on human cervical cancer (HeLa) and human promyelocytic leukemia (HL-60) cells showed an enhanced cellular uptake because of charge-conversion and exhibited a higher cell-killing performance. Moreover, the graft ratio of DOX and 6MP showed the ability to adjust the cytotoxicity; the micelles with a graft ratio of 2: 1 (M(DOX 2 /6MP)) displayed the higher cellular inhibition on either HeLa (combination index (CI) = 0.62) or HL-60 (CI = 0.35) cells. Overall, this novel dual-drug-conjugated delivery system might have important potential applications for combination therapy of cancer., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Nanoparticles coupled with targeting moieties have attracted a great deal of attention for cancer therapy since they can facilitate site-specific delivery of drug and significantly limit the side effects of systemic chemotherapy. In this study, our aim is to develop surface functionalized hydroxyapatite nanoparticles, which could provide binding sites for a cancer cell targeting ligand, folic acid (FA) as well as an anticancer drug, doxorubicin hydrochloride (DOX). In order to attain dual functionalities, hydroxyapatite nanoparticles were functionalized with gelatin molecules. Gelatin, being a protein has both carboxyl and amine moieties, which makes it suitable for binding of DOX and FA. FA was chemically conjugated to the nanoparticles through an EDCNHS coupling reaction. The formation of single-phase hydroxyapatite nanostructure was ascertained by X-ray diffraction studies and the presence of organic moieties on the surface of nanoparticles was evident from Fourier transform infrared spectroscopy, thermogravimetric analysis and U.V.-visible spectroscopy. The FA-conjugated nanoparticles (FA-Gel-HANPs) showed high affinity towards DOX and pH-responsive sustained release of drug with higher release rate under acidic pH conditions, desired for cancer therapy. The FA-Gel-HANPs showed negligible cytotoxicity towards different cell lines (HepG2, WEHI-164, KB, WI-26 VA4 and WRL-68). However, DOX loaded nanoparticles (DOX-FA-Gel-HANPs) exhibited significant toxicity towards these cells, which was however highest in folate receptor (FR)-overexpressing, KB cells. These results were correlated with enhanced cellular uptake of DOX-FA-Gel-HANPs in KB cells in comparison to FR-deficient, WRL-68 cells studied by confocal laser scanning microscopy and flow cytometry. Moreover, cell cycle analysis in KB cells, showed higher sub-G1 population, indicating apoptosis as one of the cell death mechanisms. Overall, this study suggests that DOX-FA-Gel-HANPs could serve as a promising tumor-targeted drug delivery system., Competing Interests: Declaration of Competing Interest There are no conflicts of interest to declare., (Copyright © 2019 Elsevier B.V. All rights reserved.)

In this paper, a targeting hyaluronic acid (HA)/mesoporous silica nanoparticle (MSN) based drug delivery system (DDS) with dual-responsiveness was prepared for cancer therapy. To avoid the side reaction between the anti-cancer drug doxorubicin hydrochloride (DOX) and HA, host-guest interaction was applied to fabricate the DDS named DOX@MSN-SS-N=C-HA. The "nanocontainer" MSN was modified with benzene ring via both pH-sensitive benzoic imine bond and redox-sensitive disulfide linkage. When DOX was loaded in the pores of MSN, the channels were then capped by the "gatekeeper" β-CD grafted HA (HA-g-CD) through host-guest interaction between β-CD and benzene. HA endowed the drug carriers with the targeting capability in CD44 over-expressed cancer cells. After cellular uptake, the carriers could rapidly release DOX for cell apoptosis due to both the hydrolysis of benzoic imine bond at low pH and the cleavage of disulfide bond at a high concentration of glutathione (GSH) intracellular. In vitro drug release studies and in vitro cytotoxicity studies were taken to investigate the dual-responsiveness of the carriers. And the CD44-receptor mediated cancer cell targeting capability was investigated as well. In conclusion, the targeted dual-responsive complex DDS fabricated through host-guest interaction has promising potential in cancer therapy., (Copyright © 2019. Published by Elsevier B.V.)

Cells in the center of solid tumors have always been an abyss untouched by treatments because of their deep location and increased drug resistance. Herein, we designed a rational strategy for sequential intra-intercellular delivery of nanomedicine to deep sites of drug-resistant solid tumors. In our formulation, dopamine and hemoglobin were polymerized to form a smart nanocarrier (PDA/Hb). Subsequently, the doxorubicin and nitric oxide donor were connected on the surface of PDA/Hb to obtain D/N-PDA/Hb. Ultimately, the hyaluronic acid was combined with D/N-PDA/Hb to form D/N-PDA/Hb@HA. Concretely, acidic and neutral environments of tumor cells were treated as a switch to turn on or off the drug release of a nanodrug. Meanwhile, the generation of nitric oxide in situ was exploited to favor the lysosomal escape of nanocarriers and overcome the drug resistance of deep solid tumor cells. The results indicated that the nanodrug based on sequential intra-intercellular delivery showed exciting penetration efficiency and resistance reversal of solid tumors. Conventional nanodrug delivery was highly dependent on the enhanced permeability and retention (EPR) effect and limited by tumorous interstitial fluid pressure. Plenty of drugs stayed on the surface of solid tumors, and the infiltrated drugs were inefficient due to strict resistance. To conquer this dilemma, this work proposed a new mechanism reversing the EPR effect for drug delivery, leading to better penetration and resistance reversal of solid tumors.

A novel hybrid drug nanocarrier is developed with CuCo 2 S 4 nanoparticles as the core to be encapsulated by poly(ionic liquid) (PIL), that is, poly(tetrabutylphosphonium styrenesulfonate) (P[P 4,4,4,4 ][SS]), as the shell. Doxorubicin (DOX) is loaded onto the PIL shell via electrostatic attraction involving amine in DOX and styrenesulfonate in PIL. pH- and thermal-responsive characteristics of P[P 4,4,4,4 ][SS] endow the multifunctional hybrid nanocarrier system DOX-CuCo 2 S 4 @PIL with sensitive dual-stimuli-triggered drug release behaviors. The CuCo 2 S 4 core converts near-infrared (NIR) irradiation into thermal energy to trigger the shrinkage of the PIL shell, which subsequently promotes drug release, and the pH-responsive release of DOX involves pH-sensitive electrostatic interaction of the PIL shell with DOX. A favorable controlled release of 90.5% is achieved under pH/thermo dual stimuli. In vitro experiments with MCF-7 cells well demonstrated that the drug release is controlled by the acidic intracellular environment with NIR irradiation. The CuCo 2 S 4 core also serves as a photoacoustic (PA) imaging contrast agent, as demonstrated by in vivo treatment of the MCF-7-carrying mice.

We describe a novel class of stimuli-sensitive sulfonium-based synthetic lipids, which exhibit several favorable biophysical properties of phospholipids. The potent sulfonium-based lipid was successfully disassembled by glutathione to release the encapsulated drug molecules in a controlled manner. The cationic lipid also showed lower cytotoxicity against mammalian cells and displayed moderate antibacterial activities.

Polymer nanoparticulate drug delivery systems that respond to reactive oxygen species (ROS) and glutathione (GSH) simultaneously at biologically relevant levels hold great promise to improve the therapeutic efficacy to cancer cells with reduced side effects of chemo drugs. Herein, a novel redox dual-responsive amphiphilic block copolymer (ABP) that consists of a hydrophilic poly (ethylene oxide) block and a hydrophobic block bearing disulfide linked phenylboronic ester group as pendant is synthesized, and the DOX loaded nanoparticles (BSN-DOX) based on ABPs with varied hydrophobic block length are fabricated for DOX delivery. The self-immolative leaving reaction of phenylboronic ester triggered by extracellular ROS and the cleavage of disulfide linkages induced by intracellular GSH both lead to rapid DOX release from BSN-DOX, resulting in an on-demand DOX release. Moreover, BSN-DOX show better tumor inhibition and lower side effects in vivo compared with free drug., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

To enhance the tumor-targeting and tumor cell-specific drug-release capacity of nano drug delivery systems, a magnetic resonance imaging-traceable, magnetic-targeted nanoplatform is developed, and the nanoplatform is prepared by capping mesoporous silica (MSN)-coated iron oxide nanoparticles (IONPs) with programmable DNA hairpin sensor "gates." In normal cells (HL-7702, human liver cells), the nanoplatform is able to entrap the loaded drugs, showing an "OFF" state; the nanoplatform is activated by endogenous miRNA-21 overexpressed in tumor cells (HepG2, human liver tumor cells), which serve as an exclusive key to unlock the nanoplatform through hybridization with programmable DNA hairpin, leading to a rapid drug release, showing an "ON" state. The nanoplatform exhibits high antitumor efficacy and low toxicity in in vitro and in vivo studies owing to its magnetic targeting and tumor cell-activated properties, paving the way for targeted and personalized tumor treatment and showing potential for clinical applications., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Doxorubicin (DOX) has antitumor effects mediated by cell viability inhibition and by inducing cellular apoptosis. However, it has limited use in clinical applications due to various factors such as hydrophobicity, dose-dependent toxicity effects on normal tissues, short cycle retention time, and low targeting ability. This study aims at enhancing hydrophilicity of DOX to restrict its toxic effects to within or around the tumor sites and also to improve its targeting ability to enhance antitumor efficiency., Methods: Micelles composed of biodegradable poly (ethylene glycol)-poly (lactic acid) copolymers (PEG-PLA) were employed to deliver DOX via a self-assembly method and were coupled to VEGF antibodies. The morphology, size, and physical stability of PEG-PLA-DOX targeting VEGF micelles (VEGF-PEG-PLA-DOX micelles) were assessed. Then, the release ability of DOX from these micelles was monitored, and their drug loading capacity was calculated. MTT assay revealed the in vitro antitumor effect of VEGF-PEG-PLA-DOX micelles. Moreover, ROS release was measured to evaluate apoptotic effects of these nanoparticle micelles. In vivo therapeutic efficiencies of VEGF-PEG-PLA-DOX micelles on a lung cancer nude mouse model was evaluated., Results: DOX-loaded micelles were obtained with a drug loading capacity of 12.2% and were monodisperse with 220 nm average diameter and a controlled in vitro DOX release for extended periods. In addition, VEGF-PEG-PLA-DOX micelles displayed a larger cell viability inhibitory effect as measured via MTT assays and greater cell apoptosis induction through in vitro ROS levels compared with PEG-PLA-DOX micelles or free DOX. Furthermore, VEGF-PEG-PLA-DOX micelles could improve in vivo antitumor effects of DOX by reducing tumor volume and weight., Conclusions: VEGF-PEG-PLA-DOX micelles displayed a larger anti-tumor effect both in in vitro A549 cells and in an in vivo lung cancer nude mouse model compared with PEG-PLA-DOX micelles or free DOX, and hence they have potential clinical applications in human lung cancer therapy.

Multidrug resistance (MDR) remains one of the most important challenges to clinical chemotherapeutics. In this study, versatile mimic vesicles (MVs) derived from erythrocytes were investigated as delivery systems for siRNA and doxorubicin (DOX) to treat MDR tumors. The carriers could be readily obtained through extruding erythrocyte membranes and had the advantages of biological homogeneity, high output, controllable size, low cost, and excellent biocompatibility. Moreover, aptamers modified on the MVs endowed the carriers with tumor-targeting capacity. DOX and P-glycoprotein (P-gp) siRNA were loaded onto the MVs through incubation and cholesterol-mediated methods, achieving high loading rates and targeted tumor delivery. The drug-loaded carriers could successfully overcome drug resistance and synergistically kill MDR tumors through P-gp silencing and DOX-induced growth inhibition. This MV-based drug delivery system therefore provides new insights into the synergistic targeting of MDR tumors and offers an alternative delivery strategy to overcome MDR.

Recent drug delivery nanosystems for cancer treatment still suffer from the poor tumor accumulation and low therapeutic efficacy due to the complex in vivo biological barriers. To resolve these problems, in this work, a novel gradient redox-responsive and two-stage rocket-mimetic drug nanocarrier is designed and constructed for improved tumor accumulation and safe chemotherapy. The nanocarrier is constructed on the basis of the disulfide-doped organosilica-micellar hybrid nanoparticles and the following dual-functional modification with disulfide-bonded polyethylene glycol (PEG) and amido-bonded polyethylenimine (PEI). First, prolonged circulation duration in the bloodstream is guaranteed due to the shielding of the outer PEG chains. Once the nanocarrier accumulates at the tumoral extracellular microenvironment with low glutathione (GSH) concentrations, the first-stage redox-responsive behavior with the separation of PEG and the exposure of PEI is triggered, leading to the improved tumor accumulation and cellular internalization. Furthermore, with their endocytosis by tumor cells, a high concentration of GSH induces the second-stage redox-responsiveness with the degradation of silsesquioxane framework and the release of the encapsulated drugs. As a result, the rocket-mimetic drug carrier displays longer circulation duration in the bloodstream, higher tumor accumulation capability, and improved antitumor efficacy (which is 2.5 times higher than that with inseparable PEG). It is envisioned that the rocket-mimetic strategy can provide new solutions for improving tumor accumulation and safety of nanocarriers in further cancer chemotherapy.

Most of the existing single-component nanostructures cannot provide comprehensive diagnostic information, and their treatment strategies always have to combine other therapeutics as a complementary for effective biomedical application. Here, we adopted a facile approach to design a theranostic nanoflower (NF) with robust efficacy for comprehensive tumor diagnosis and quadruple synergistic cancer therapy. The NF is equipped with a metallic hybrid of several functional elements and flower-like superstructures and thus shows excellent in vitro and in vivo theranostic performance. It shows high X-ray attenuation coefficiency for the Bi element, strong near-infrared (NIR) plasmon absorbance and singlet oxygen ( 1 O 2 ) generation ability for the Mo element, and great photothermal conversion efficiency (54.7%) because of enhanced photoabsorption of the petal structure. Moreover, the NF realizes a very high doxorubicin-loading efficiency (90.0%) and bimodal pH/NIR-responsive drug release, posing a promise as a controlled drug carrier. The NF also shows excellent performance at trimodal magnetic resonance/X-ray computed tomography/photoacoustic imaging for comprehensive tumor diagnosis. To our best knowledge, it is the first time that integrating at least seven functions into one biomedical nanomaterial for well-rounded tumor theranostics has been reported. This "all-in-one" NF opens a new perspective in developing novel and efficient multifunctional nanotheranostics.

Photosensitive supramolecular micelles, a combination of intermolecular hydrogen bonds between complementary adenine (A) and uracil (U) groups and a blend of two types of supramolecular polymers, can stably self-assemble into structurally stable, spherical micelles in aqueous solution before and after photoirradiation. The resulting micelles possess unique amphiphilic properties, photo-induced tunable phase-transition behavior, excellent biocompatibility, well-controlled spherical morphology, and can be tailored in size. Moreover, the drug content and entrapment efficiency can be finely tuned, and release kinetics can be modulated using combinations of changes in temperature and photoirradiation, making these micelles highly addictive as drug nanocarriers. Importantly, cytotoxicity assays and flow cytometric analyses confirmed that drug-loaded irradiated micelles exerted more potent cytotoxic effects against cancer cells and exhibited much higher cellular uptake efficiency than the free drug and drug-loaded nonirradiated micelles, indicating that the drug-loaded irradiated micelles rapidly entered the tumor cells to induce massive cell death. Therefore, this newly-developed supramolecular system could serve as a safe, efficient nanocarrier to effectively inhibit the growth and spread of primary tumors.