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For the past few years, organic-inorganic hybrid nanocarriers have been widely explored for effective drug delivery and preferable disease treatments. In this article, hydrothermal method was utilized to prepare fine dispersed layered double hydroxide (Mg-Al LDH) suspension. Polyethylene glycol (PEG) was grafted on the surface of LDH lamella in order to improve the dispersibility of LDH. Besides, the anti-cancer drug gemcitabine was grafted on the surface of LDH lamellas through chemical grafting. Hence a novel new type of organic-inorganic hybrid drug delivery system LDH-mPEG-Gemcitabine was obtained. In addition, the siRNA was intercalated into the LDH interlamination by ion exchange method to realize drug and gene co-delivery. The loading capacity of LDH and LDH-mPEG-Gemcitabine was evaluated by agarose gel electrophoresis. The characterization by laser particle size analyzer, TEM, FT-IR, XRD

Prodrug and drug delivery systems are two effective strategies for improving the selectivity of chemotherapeutics. Molecularly imprinted polymers (MIPs) have emerged as promising carriers in targeted drug delivery for cancer treatment, but they have not yet been integrated with the prodrug strategy. Reported here is an MIP‐based smart prodrug delivery system for specific targeting, prolonged retention time, and tumor microenvironment‐triggered release. 5′‐Deoxy‐5‐fluorocytidine (DFCR) and sialic acid (SA) were used as a prodrug and a marker for tumor targeting, respectively. Their co‐imprinted nanoparticles were prepared as a smart carrier. Prodrug‐loaded MIP specifically and sustainably accumulated at the tumor site and then gradually released. Unlike conventional prodrug designs, which often require in‐liver bioconversion, this MIP‐based prodrug delivery is liver‐independent but tumor‐dependent. Thus, this study opens new access to the development of smart prodrug delivery nanoplatforms., A molecularly imprinted polymer (MIP) based smart prodrug delivery nanoplatform was demonstrated with the ability to specifically target tumor sites with prolonged retention time and gradual tumor microenvironmental pH‐triggered release. The MIP‐based prodrug delivery is liver‐independent but tumor‐dependent, which not only greatly enhances tumor specificity but also expands the scope of applicable prodrugs.

Laser desorption ionization mass spectrometry (LDI-MS) has been developed to be an essential tool for the analysis and identification of a large variety of species, ranging from small metabolites, drugs and pollutants to peptides and proteins and even to bacteria. Matrix assisted LDI-MS has shown a great power for macromolecules, but its analytical capability to low mass compounds is limited due to inherent drawbacks, including abundant interference in low mass range (800 Da) caused by matrix self-dissociation and poor reproducibility due to inhomogeneous crystallization. Several matrix-free methods have been developed to solve these issues, mainly through altering organic matrix with inorganic nanostructured surfaces or nanomaterials as LDI medium. In the past five years, improvements on conventional silicon-based, metal-based, metal oxide-based and carbon-based LDI media as well as emerging novel materials such as 2D nanomaterials and organic frameworks have gained important progresses. Meanwhile, with the deep research in light-matter interaction, LDI mechanism studies begin to grow and become to attach great importance. Advances in both medium and mechanism promote to expand the applicable potential of nanostructure/nanomaterial-assisted LDI-MS in many aspects, including trace analysis, structural analysis and MS imaging. In this review, we survey the major progresses in this area in recent years. We also sketch remaining challenges and directions for future development.

Although protein therapeutics is of significance in therapeutic intervention of cancers, controlled delivery of therapeutic proteins still faces substantial challenges including susceptibility to degradation and denaturation and poor membrane permeability. Herein, we report a sialic acid (SA)-imprinted biodegradable silica nanoparticles (BS-NPs)-based protein delivery strategy for targeted cancer therapy. Cytotoxic ribonuclease A (RNase A) was effectively caged in the matrix of disulfide-hybridized silica NPs (encapsulation efficiency of ∼64%), which were further functionalized with cancer targeting capability via surface imprinting with SA as imprinting template. Such nanovectors could not only maintain high stability in physiological conditions but also permit redox-triggered biodegradation for both concomitant release of the loaded therapeutic cargo andiin vivo/iclearance.iIn vitro/iexperiments confirmed that the SA-imprinted RNase A@BS-NPs could selectively target SA-overexpressed tumor cells, promote cells uptake, and subsequently be cleaved by intracellular glutathione (GSH), resulting in rapid release kinetics and enhanced cell cytotoxicity.iIn vivo/iexperiments further confirmed that the SA-imprinted RNase A@BS-NPs had specific tumor-targeting ability and high therapeutic efficacy of RNase A in xenograft tumor model. Due to the specific targeting and traceless GSH-stimulated intracellular protein release, the SA-imprinted BS-NPs provided a promising platform for the delivery of biomacromolecules in cancer therapy.

The purpose of this study was to fabricate a novel binary hydrogel, and the insulin-loaded hydrogel was used as rectal suppository to prevent type I diabetes. The binary hydrogel was synthesized via solution polymerization. Its structure was studied by Fourier transform infrared spectroscopy (FTIR) and Raman spectra. The swelling behaviors of binary hydrogels were revealed in pH 1.2, 6.8 and 7.4 buffers, respectively. Their inner morphologies were observed with a scanning electron microscope (SEM). Insulin (INS) was selected as a model drug and encapsulated into the binary hydrogels. INS release study was carried out in pH 7.4 buffer. The hypoglycemic effects of INS-loaded hydrogels were studied by rectal administration. FTIR and Raman spectra confirmed the obtaining of binary hydrogels. The hydrogel showed a high swelling ratio in pH 7.4 (rectum environment). SEM photographs illustrated that many micro-pores in the inner of binary hydrogels, which could accommodate abundant guest molecule (e.g. INS). INS release profile suggested that INS-loaded hydrogels could diffuse INS at a sustained manner. Animal studies proved that INS-loaded binary hydrogel had an obvious hypoglycemic effect. Therefore, it could be speculated that the binary hydrogel had a potential application on treating type I diabetes by rectal administration.

The vanadium oxide V2O5•4VO2 cathode material has aroused significant interest due to its high theoretical capacity and wide availability. However, the poor rate and cycle performance of the V2O5•4VO2 electrode severely hindered its further application in high-energy density lithium-ion batteries. Herein, a kind of Al/Mn co-doped V2O5•4VO2 prepared via facile solvothermal method combined with annealing process was reported. Theoretical and experimental results reveal that [AlO6] and [MnO6] not only serve as an octahedral pillar to extend the interlayer spacing, but introduce oxygen vacancies that provide more lithium ion active sites and higher ionic and electronic conductivity in lithium ion (de)intercalation process. Paired with lithium metal anode, Al/Mn co-doped V2O5•4VO2 cathode exhibits better performance metrics of 322.5 mAh/g at 0.1 A/g, 91.7% capacity retention after 50 cycles, and 195.8 mAh/g after 200 cycles at a current density of 1 A/g, while the values corresponding to the pure phase V2O5•4VO2 are 248.7 mAh/g, 66.9% as well as 97.7 mAh/g respectively. Actually, the insight into the performance of potential electrode materials improved by double ion doping was provided in the present work.

Environmental pollution caused by sulfide compounds has become a major problem for public health. Hence, accurate detection of sulfide anions (S2−) level is valuable and vital for environmental monitoring and protection. Here, we report a new colorimetric/fluorescent dual-mode sensor for the determination of S2− based on the inhibition of enzyme activity and the unique optical properties of produced 2,3-diaminophenazine (DAP), thus making the analytical results more convincing. In this strategy, horseradish peroxidase (HRP) enzyme is used for catalyzing the H2O2-mediated oxidation of o-phenylenediamine (OPD) to produce DAP, and the color changed to bright yellow and produced orange yellow fluorescence. But the presence of S2− could cause the deactivation of HRP, which decreased the amount of DAP and consequently resulted in a substantial SPR band fading and an evident fluorescence quenching simultaneously. The mechanism of S2− sensor was examined by combining the UV–vis absorption spectra, fluorescence spectra and electrospray ionization mass spectrometry analysis. Under optimal conditions, the colorimetric and fluorescent linear responses of the proposed method exhibited a wide linear range from 2.5 nM–7.5 μM with ultralow detection limits of 1.2 nM and 0.9 nM, respectively. Some potential interferents (such as F−, Cl−, Br−, I−, SO42−, SO32−, SCN−, H2PO4−, HPO42−, Ac−, NO3−, CO32−) in real samples showed no interference. Moreover, the proposed method offered advantages of simple, low-cost instruments and rapid assay without the utilization of nanomaterials and has been successfully applied to determine S2− content in lake water samples with satisfying recoveries over 97.6%. More importantly, the present S2− sensor not only afforded a new optical sensing pattern for bioanalysis and environment monitoring, but also extends the application field of HRP-catalyzed OPD–H2O2 system.

Bioceramic particulates capable of filling bone defects have gained considerable interest over the last decade. Herein, dual-shell bioceramic microspheres (CaP@CaSi@CaP, CaSi@CaP@CaSi) with adjustable beta-tricalcium phosphate (CaP) and beta-calcium silicate (CaSi) distribution were fabricated using a co-concentric capillary system enabling bone repair via a tailorable biodegradation process. The in vitro results showed the optimal concentration (1/16 of 200 mg/ml) of extracts of dual-shell microspheres could promote bone marrow mesenchymal cell (BMSC) proliferation and enhance the level of ALP activity and Alizarin Red staining. The in vivo bone repair and microsphere biodegradation in calvarial bone defects were compared using micro-computed tomography and histological evaluations. The results indicated the pure CaP microspheres were minimally resorbed at 18 weeks post-operatively and new bone tissue was limited; however, the dual-shell microspheres were appreciably biodegraded with time in accordance with the priority from CaSi to CaP in specific layers. The CaSi@CaP@CaSi group showed a significantly higher ability to promote bone regeneration than the CaP@CaSi@CaP group. This study indicates that the biphasic microspheres with adjustable composition distribution are promising for tailoring material degradation and bone regeneration rate, and such versatile design strategy is thought to fabricate various advanced biomaterials with tailorable biological performances for bone reconstruction.

A novel injectable and high-solid-content drug-loaded supramolecular hydrogel (PTX-mPECT NP/α-CDgel) was prepared by self-assembly of inclusion complexes based on PTX-loaded mPECT (methoxy poly(ethylene glycol)-b-poly(e-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-un-decanone)) nanoparticles (PTX-mPECT NPs) and α-cyclodextrin (α-CD). Paclitaxel (PTX) was chosen as a hydrophobic drug encapsulated into mPECT NPs. Then, gelation occurred when the aqueous solution of α-CD was added to the PTX-mPECT NPs aqueous dispersion within several seconds after stirring. Importantly, with the erosion of the hydrogel, PTX-loaded NPs could be released again and then PTX released further. Rheological studies showed that PTX-mPECT NP/α-CDgel with good injectability underwent a shear-induced sol-gel transition. The results of in vitro drug-release studies demonstrated a sustained-release profile, and the cumulative release of PTX was ≈35% after 20 days. The results of cell-uptake studies and in vitro cytotoxicity studies indicated that the PTX-loaded NPs have been efficiently delivered to cells and killed tumor cells. Higher suppression of tumor growth demonstrated the remarkable anticancer effect of PTX-mPECT NP/α-CDgel upon peritumoral injection. These results showed that high-solid-content PTX-mPECT NP/α-CDgel based on in situ systems could be a promising candidate for local and sustained drug delivery.

Intraperitoneal (IP) chemotherapy is a preferable treatment option for peritoneal carcinomatosis of malignancies by delivering chemotherapeutic drugs into the abdominal cavity. A persistent major challenge in IP chemotherapy is the need to provide effective drug concentration in the peritoneal cavity for an extended period of time. In the present work, the thermosensitive hydrogel system (PTX/PECT(gel)) assembled by PTX (paclitaxel)-loaded amphiphilic copolymer (PECT, poly (ε-caprolactone-co-1,4,8-trioxa [4.6]spiro-9-undecanone)-poly(ethylene glycol)-poly (ε-caprolactone-co-1,4,8-trioxa [4.6]spiro-9-undecanone)) nanoparticles was developed for sustained IP chemotherapy of peritoneal carcinomatosis model. Cytotoxicity assay indicated that PECT hydrogel was biocompatible with very low cytotoxicity and PTX/PECT(gel) had enhanced cytotoxicity than free PTX. In vivo toxicity study demonstrated the biocompatibility and biosafety of PECT hydrogel as an IP chemotherapy carrier. The fluorescence imaging method was employed to monitor the intraperitoneal degradation of PECT hydrogel by labeling PECT with rhodamine B. PECT hydrogel with the dose of 200μL showed about 8days' retention time and most of the injected hydrogel was located in the intestine. The anti-tumor efficacy study was carried out in mice bearing CT26 intraperitoneal ascites fluid as colorectal peritoneal carcinomatosis model. The result showed that intraperitoneal administration of PTX/PECT(gel) could effectively suppress growth and metastasis of CT26 peritoneal carcinomatosis in vivo, compared with Taxol® group. The pharmacokinetic studies demonstrated that PTX/PECT(gel) could improve the bioavailability of PTX by being formulated in PECT hydrogel. Overall, sustained drug concentration at peritoneal levels in combination with drug in the form of nanoparticle contributes to the enhanced anti-tumor efficacy. Thus, our results suggested that PTX/PECT(gel) may have great potential applications in IP chemotherapy.

Injectable and biodegradable supramolecular hydrogel mPECT NP/α-CD(gel) composed of high-concentration nanoparticle dispersion (≤20% W/V) and α-cyclodextrins (α-CD) are prepared by a two-level physical cross-linking using amphiphilic block polymer methoxy poly(ethylene glycol)-b-poly(ε-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone) (mPECT) and α-CD. The gelation behavior depends on the concentration of nanoparticles and α-CD. The viscoelasticity and shear thinning of mPECT NP/α-CD(gel) are confirmed. In vitro hydrogel erosion is demonstrated to be mainly a concentration-dependent dissociation process with general release of discrete mPECT nanoparticles about 50 nm that can be easily taken up by cells. The in vitro release behavior can be modulated by changing the concentration of nanoparticles or α-CD. In vitro and in vivo cytotoxicity study demonstrates its biocompatibility and biosafety. Gel formation after subcutaneous injection is also confirmed and mPECT NP/α-CD(gel) shows about 2 weeks retention time. This work validates the potential application for this supramolecular hydrogel in local and sustained delivery of nanoparticles.

In this study, the copolymer of methoxy poly(ethylene glycol) methacrylate-co-poly(methylacrylic acid) [poly(mPEGMA-co-MAA)] was synthesized via radical polymerization. Based on this copolymer, novel chitosan-modified poly(mPEGMA-co-MAA) nanoparticles (CS/NPs) were developed to improve the bio-availability of ibuprofen (IBU). Fourier transform infrared spectroscopy (FTIR) and 1H nuclear magnetic resonance (1H NMR) spectra were used to confirm the synthesis of the copolymers. The morphology of CS/NPs was investigated with transmission electron microscopy (TEM). Thermogravimetric analysis (TGA) was used to reveal the thermodynamic properties of the CS/NPs. The cytotoxicity of CS/NPs was assessed by the cell viability of 293T cells. FTIR and 1H NMR spectra confirmed the synthesis of the novel copolymer. TEM photographs showed that the CS/NPs had a core-shell structure. High cell viability indicated that the CS/NPs were nontoxic. The in vitro release profiles suggested that the CS/NPs released IBU in pH 7.4 buffer in a continuous manner. Furthermore, the IBU-CS/NPs showed a long antifebrile effect. Animal experiments showed that the IBU-CS/NPs had obvious antifebrile effects. Therefore, CS/NPs could reduce the dosing frequency of IBU, and improve its bio-availability.

The application of PEG-b-PCL micelles was dampened by their inherent low drug-loading capability and relatively poor cell uptake efficiency. In this study, a series of novel PEG-b-PCL copolymers methoxy poly(ethylene glycol)-b-poly(ε-caprolactone-co-γ-dimethyl maleamidic acid -ε-caprolactone) (mPEG-b-P(CL-co-DCL)) bearing different amounts of acid-labile β-carboxylic amides on the polyester moiety were synthesized. The chain structure and chemical composition of copolymers were characterized by (1)H NMR, Fourier transform infrared spectroscopy (FT-IR), and gel permeation chromatography (GPC). mPEG-b-P(CL-co-DCL) with critical micellar concentrations (CMCs) of 3.2-6.3 μg/mL could self-assemble into stable micelles in water with diameters of 100 to 150 nm. Doxorubicin (DOX), a cationic hydrophobic drug, was successfully encapsulated into the polymer micelles, achieving a very high loading content due to electrostatic interaction. Then the stability, charge-conversional behavior, loading and release profiles, cellular uptake and in vitro cytotoxicity of free drug and drug-loaded micelles were evaluated. The β-carboxylic amides functionalized polymer micelles are negatively charged and stable in neutral solution but quickly become positively charged at pH 6.0, due to the hydrolysis of β-carboxylic amides in acidic conditions. The pH-triggered negative-to-positive charge reversal not only resulted in a very fast drug release in acidic conditions, but also effectively enhanced the cellular uptake by electrostatic absorptive endocytosis. The MTT assay demonstrated that mPEG-b-P(CL-co-DCL) micelles were biocompatible to HepG2 cells while DOX-loaded micelles showed significant cytotoxicity. In sum, the introduction of acid-labile β-carboxylic amides on the polyester block in mPEG-b-P(CL-co-DCL) exhibited great potentials for the modifications in the stability in blood circulation, drug solubilization, and release properties, as well as cell internalization and intracellular drug release.

The improvement of the solid content of the hydrophobic drugs (such as paclitaxel (PTX), etc.) loaded nanoparticles (NPs) dispersion is important for enhancing drug-loaded efficiency and reducing the cost in production and application. A diblock copolymer methoxy poly(ethylene glycol)-b-poly(ε-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone) (mPECT) is synthesized via the ring-opening polymerization of ε-caprolactone and 1,4,8-trioxa[4.6]spiro-9-undecanone (TOSUO) with methoxy poly(ethyleneglycol) (mPEG） as the initiator. The chemical structures and thermal properties of mPECT are characterized by (1)HNMR, Fourier transform infrared (FT-IR), gel permeation chromatography, differential scanning calorimetry, etc. PEG45.45-b-P(C28.33-co-T5.38) (mPECT-2) is able to self-assemble into stable NPs in water via nanoprecipitation method at a high solid content (≤25 wt%) and their freeze-dried powders can well re-disperse in water. The paclitaxel (PTX) is chosen as a hydrophobic drug model and successfully encapsulate into the mPECT-2 NPs via the same method at a high solid content. The encapsulation efficiency, cytotoxicity and in vitro release of PTX-loaded NPs are investigated. The results suggest that the behavior of the drug-loaded mPECT-2 NPs prepared at a solid content of 25 wt% is similar to that of NPs prepared at a solid content of 1 wt%, which indicate that increasing solid content of polymer has no negative effect on the properties of NPs dispersion in application. In summary, the freeze-dried NPs prepared from the high solid content dispersion (≤25 wt%) has a good redispersibility and exhibits great potential in cost control of preparing NPs dispersion used as drug delivery system.

Embelin, an active ingredient of traditional herbal medicine, is used to treat many diseases such as cancer. However, embelin is hydrophobic and insoluble in water, which makes it unsuitable for in vivo applications. In this study, we constructed an embelin-loaded thermosensitive injectable hydrogel system that we named Embelin/PECT(gel) based on the amphiphilic triblock copolymer of poly (ε-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone)-poly (ethylene glycol)-poly (ε-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone) (PECT). The cytotoxicity and the antitumor effects of Embelin/PECT(gel) on mouse hepatic cancers were investigated in vitro and in vivo. Results indicated that embelin was formulated in PECT hydrogel and could be continuously released from Embelin/PECT(gel) , showing a higher cytotoxicity for H22 cells in vitro compared with free embelin. The aqueous solution of Embelin/PECT(gel) transformed into gel at the injection site within seconds, which later eroded and degraded over time in vivo. A single local peritumoral injection of Embelin/PECT(gel) in liver at a low dosage of 0.5 mg per mouse exhibited a significant antitumor effect, which was comparable to the antitumor effect of the embelin solution treatment at a total dose of 6 mg per mouse in mouse hepatic cancer. Embelin/PECT(gel) , as a drug delivery system in liver, represents a novel therapeutic drug candidate for the clinical treatment of advanced hepatocellular carcinoma.

For in situ thermosensitive hydrogels, it is a big challenge to achieve high drug loading, long-term local retention, and effective drug release simultaneously. To address these issues, we combined the strategy of drug nanocrystals (NCs) and thermosensitive hydrogels with higher gel strength. In particular, we developed paclitaxel NC-based hydrogels using PECT, a thermosensitive polymer synthesized by us (PTX-NC-PECT), and a nanoparticle-based system was used as the control (PTX-NP-PECT). First, high levels of PTX could be loaded in both PECT hydrogels. Moreover, in vivo near infrared fluorescence (NIRF) imaging showed that both hydrogel systems were able to maintain the payloads of 1,1-dioctadecyltetramethyl indotricarbocyanine iodide (DiR) at a peri-tumoural site for at least 21 days, much longer than that achieved with the control hydrogel of Pluronic® F127. Furthermore, we observed that PTX-NCs released free PTX more effectively and homogeneously than PTX-NPs in vitro. It was further verified in vivo that the release of DiR from DiR-NC-PECT was more complete than that from DiR-NP-PECT. Finally, PTX-NC-PECT gel demonstrated the strongest anti-tumour efficacy on MCF-7 breast cancer. In conclusion, PTX-NC-PECT hydrogel might be a high-performance thermosensitive hydrogel for local cancer therapy.

Nanoparticle (NP)-assisted drug delivery systems with disassemblable behaviors in response to intracellular microenvironment are urgently demanded in systemic cancer chemotherapy for enhanced intracellular drug release. Curcumin (CUR), an effective and safe anticancer agent, was limited by its water insolubility and poor bioavailability. Herein, pH and reduction dual-induced disassemblable NPs for high loading efficiency and improved intracellular release of CUR were developed based on an acid degradable cyclic benzylidene acetal groups (CBAs)-functionalized poly(2,4,6-trimethoxybenzylidene-1,1,1-tris(hydroxymethyl)ethane methacrylate)-g-SS-poly(ethylene glycol) (PTTMA-g-SS-PEG) graft copolymer, which was readily prepared via RAFT copolymerization and coupling reaction. The NPs self-assembled from PTTMA-g-SS-PEG copolymers were stable at physiological pH, and quickly disassembled in mildly acidic and reductive environments because of the hydrolysis of CBAs in hydrophobic PTTMA core and the cleavage of disulfide-linked detachable PEG shell. PTTMA-g-SS-PEG NPs exhibited excellent CUR loading capacity with drug loading content up to 19.2% and entrapment efficiency of 96.0%. Within 20 h in vitro, less than 15.0% of CUR was released from the CUR-loaded NPs in normal physiological conditions, whereas 94.3% was released in the presence of reductive agent and mildly acidic conditions analogous to the microenvironment in endosome/lysosome and cytoplasm. Confocal fluorescence microscopies revealed that the CUR-loaded PTTMA-g-SS-PEG NPs exhibited more efficiently intracellular CUR release for EC-109 cells than that of CUR-loaded reduction-unresponsive PTTMA-g-PEG NPs and free CUR. In vitro cytotoxicity studies displayed blank PTTMA-g-SS-PEG NPs showed low toxicity at concentrations up to 1.0 mg/mL, whereas CUR-loaded PTTMA-g-SS-PEG NPs demonstrated more efficient growth inhibition toward EC-109 and HepG-2 cells than reduction-unresponsive controls and free CUR. Therefore, the above results indicated that pH and reduction dual-induced disassemblable PTTMA-g-SS-PEG NPs may have emerged as superior nanocarriers for active loading and promoted intracellular drug delivery in systemic cancer chemotherapy.

Combination delivery systems composed of injectable hydrogels and drug-incorporated micelles or nanoparticles with tunable and convenient properties for clinical operation and storage are urgently demanded in regional cancer chemotherapy to prolong and control drug release, enhance antitumor efficiency and decrease side effects. Previously, we developed a novel thermosensitive amphiphilic triblock copolymer, poly(e-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone)–poly(ethylene glycol)–poly(e-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone) (PECT), and fabricated a reconstituted “two into one” combination system of thermosensitive injectable hydrogel PTX/PECTGel, assembled from paclitaxel (PTX)-loaded PECT nanoparticles (NPs). PTX/PECTGel could be stored as freeze-dried powders of paclitaxel-loaded PECT NPs, which could be reconstituted into aqueous fluid dispersions at ambient temperature just by mixing with water after gentle stirring for several minutes, and form a hydrogel at the injected site in vivo. Herein, the drug release, in vivo morphology, antitumor efficiency and pharmacokinetic properties of PTX/PECTGel were evaluated. The PTX/PECTGel combination system could continuously release PTX in a near linear manner over 42 days in vitro, and simultaneously, PTX/PECT NPs containing 75% of the total released PTX could dissociate from the PTX/PECTGel. PTX/PECTGel exhibited remarkable in vitro anti-proliferative activities against Ehrlich ascites carcinoma (EAC) cancer cells. The peritumorally or intratumorally injected PECT gel could cover the entire surface or fill up the interior space of the tumor, respectively. A single peritumoral injection of the PTX/PECTGel formulation at a low dosage of 10 mg kg−1 could completely inhibit the growth of an EAC tumor inoculated in Balb/c mice after the first week, and the inhibition could be sustained for more than 21 days. The plasma pharmacokinetic study demonstrated that PTX/PECTGel could greatly decrease the systemic exposure of PTX, as confirmed by the rather low plasma concentration. On the other hand, the PTX concentration in normal tissues with the intratumoral injection of PTX/PECTGel was approximately 2 μg g−1, which was 3–10 times lower than that with the intraperitoneal or intratumoral injection of Taxol®, implying fewer off-target side effects. These data confirmed that the PTX/PECTGel combination local delivery system could vastly prolong the in vitro and in vivo paclitaxel release, enhance the local tumor inhibition effect and lower the systemic exposure and tissue distribution of paclitaxel. Hence, the “two into one” PTX/PECTGel system holds underlying value for regional cancer chemotherapy.

As drug therapies become increasingly sophisticated, the synergistic benefits of two or more drugs are often required. In this study, we aimed at improving anti-tumor efficiency of paclitaxel (PTX)-incorporated thermo-sensitive injectable hydrogel by the synergy of burst release of doxorubicin hydrochloride (DOX⋅HCl). Thermosensitive injectable hydrogel composed of nanoparticles assembled from amphiphilic copolymer poly(e-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone)-poly(ethylene glycol)-poly(e-caprolaone-co-1,4,8-trioxa[4.6]spiro-9-undecanone) (PECT) was fabricated. Hydrophobic PTX and hydrophilic DOX⋅HCl were loaded simultaneously in the thermo-sensitive injectable hydrogel by a two-stage entrapment. Thermosensitive gelling behaviors of drug-loading PECT nanoparticle aqueous dispersions were studied. In vitro release profiles of PTX and DOX⋅HCl and in vivo anti-tumor effect by dual drugs from PECT hydrogel were investigated. The results showed that hydrophilic and hydrophobic drugs could be successfully entrapped in PECT hydrogel simultaneously without affecting its thermo-sensitive behavior. In vitro release profiles demonstrated the burst release of DOX⋅HCl and the sustained release of PTX. Anti-tumor effect was improved by a fast and tense attack caused by the burst release of hydrophilic DOX⋅HCl from hydrogel, which was continued by the sequent sustained release of PTX-incorporated nanoparticles and remnant DOX⋅HCl. Unintentionally, entrapped in PECT hydrogel, hydrophilic DOX⋅HCl was observed to have a sustained releasing pattern in vitro and in vivo.

The main aim of this study was to inhibit the re-crystallization of a potent antimalarial drug, artemisinin (ART), by encapsulating it in core-shell fibers via a coaxially electrospun method. The ART-infiltrated cellulose acetate (CA) solution as the core material and poly(vinyl pyrrolidone) (PVP) solution as the shell material were used to prepared ART-loaded core-shell fibers ([ART/CA]/PVP). Transmission electron microscopy images confirmed the core-shell structures of the coaxially electrospun fibers. The scanning electron microscope (SEM), X-ray diffraction, and differential scanning calorimetry were performed to characterize the physical states of ART in the fibers. It was observed that ART crystals were formed in the ART-loaded CA/PVP composite fibers (ART/CA/PVP) during the electrospinning process and increased during storage duration. While ART crystals hardly were observed in the fresh core-shell [ART/CA]/PVP fibers with high ART entrapped amount (20 wt.%) and a little was detected after 6-month storage. Fourier transform infrared spectroscopy (FTIR) results illustrated the hydrogen bonding interaction between ART and CA in the core-shell [ART/CA]/PVP fibers mainly contributed to the amorphous state of ART. Importantly, combination of the hydrophilic PVP shell and the amorphous ART in CA core, the core-shell [ART/CA]/PVP fibers provided a continued and stable ART release manner. Ex vivo permeation studies suggested the amorphous ART in the medicated core-shell fibers could permeate through the stratum corneum smoothly. Hence, the core-shell [ART/CA]/PVP fiber matrix could provide a potential application in transdermal patches.

Combining functions of multidrug co-delivery and multistep release in biocompatible membranes is an oncoming requirement for improving therapeutic process. In this paper, a kind of polymer micelle-embedded core/shell nanofibrous membranes was prepared by a simple and effective technology of coaxial electrospinning. The nanofibers were composed of hydrophobic polycaprolactone (PCL) shell layer and hydrophilic polyvinyl pyrrolidone (PVP) core in which more than 40 % (w/w) amphiphilic block copolymer mPECT micelles (mPECT Ms) were embedded. Two bioactive drugs, lincomycin hydrochloride (LH) as the anti-inflammatory drug and Vitamin E (VE) as the fibrinolysis drug, were effectively loaded in the PVP core of the fibers and mPECT Ms, respectively. The SEM and TEM figures showed the smooth core/shell nanofibers with interiorly even-distributed micelles were fabricated. The XRD patterns illustrated that drugs distributed amorphously in the composite mats without crystallization. The in vitro degradation test also gave evidence to the time consistency between the degradation time of this material and potential occurrence time of adhesion. Furthermore, the in vitro release profiles indicated that both drugs were controlled to release sustainably for more than 15 days, and multistep release pattern of the early fast release of LH companied by the slow VE release was achieved. Therefore, the polymer micelle-embedded core/shell nanofibrous membranes could provide a new strategy for therapeutic application to realize multidrug co-delivery and multistep release.

To improve the poor compatibility among different components of Drug-in-adhesive type patch, two novel plasters (Drug-in-fiber and Drug-in-adhesive/fiber) were developed based on ibuprofen (IBU)-loaded fiber mats. These fibrous mats were fabricated via electrospinning of cellulose acetate/poly(vinylpyrrolidone) composites in a binary solvent of N,N-dimethyl acetamide/acetone. Physical status studies suggested that Drug-in-fiber could inhibit IBU re-crystallization, but the active ingredients were released at a relatively slow rate due to the dual-resistance of fiber mat and adhesive matrix. To overcome this shortcoming, Drug-in-adhesive/fiber was designed by coupling medicated hydrophilic pressure sensitive adhesive and IBU-loaded fiber mat. This method endowed Drug-in-adhesive/fiber a fast IBU release rate and high permeated drug amount though simulative skins. This design separated enhancer from adhesive matrix, which guaranteed Drug-in-adhesive/fiber excellent adhesion forces. Hence, the plasters based on medicated fiber mats improved the compatibility among patch components.