A novel camptothecin (CPT) prodrug was successfully synthesized by conjugating CPT to adamantanecarboxylic acid (AD) via a cleavable disulfide linkage. The resulting CPT-ss-AD prodrug could act as a low molecular weight gelator to form molecular gels in water/water-miscible organic solvent mixture. Meanwhile, biodegradable amphiphilic block copolymer mPEG-b-P (MAC-co-DTC) (PPMD) was also employed as an organic framework together with CPT-ss-AD to form gel structure. CPT-ss-AD/PPMD gel exhibited less compact molecular arrangement but much more stability than CPT-ss-AD gel. The two kinds of gels could effectively release the original CPT under reductive condition at a near-constant rate without any initial burst. As compared to CPT-ss-AD single-component gel, the two-component gel, CPT-ss-AD/PPMD, had a significantly higher release rate of CPT, while 3-[4,5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide (MTT) assays also indicated highly potent cytotoxic activity against HeLa cells.

•Two functional peptides (TCPP and TPP) were designed and synthesized.•Highly controllable MSNs were prepared by using TCPP and TPP as gatekeepers.•The newly developed MSNs show a remarkable synergistic anticancer effect.Synergistic therapy involving two or more therapeutic agents with different anticancer mechanisms represents a promising approach to eradicate chemotherapy-refractory cancers. However, the preparation of a synergistic therapy platform generally involves complicated procedures to encapsulate different therapeutic agents and thereby increases the purification difficulty. In this work, we reported a simple but robust strategy to prepare a highly controllable drug delivery system (DDS) for synergistic cancer therapy. To construct this robust DDS, mesoporous silica nanoparticles (MSNs) were employed as a nanoplatform to encapsulate anticancer drug doxorubicin (DOX). After using a tumor-targeting cellular membrane-penetrating peptide (TCPP) and a mitochondria-targeting therapeutic peptide (TPP) to seal the surface pores via disulfide bonds, these newly developed MSNs can target cancer cells, penetrate cell membrane and rapidly release anticancer drug and mitochondria-targeted peptide in cytoplasm, inducing a remarkable synergistic anticancer effect. The new design concept reported here will promote the development of targeted and smart DDSs for synergistic cancer therapy.

Functional mesoporous silica particles have attracted growing research interest for controlled drug delivery in targeted cancer therapy. For the purpose of efficient targeting tumor cells and reducing the adverse effect of antitumor drug doxorubicin (DOX), biocompatible and enzyme-responsive mesoporous silica nanoparticles (MSNs) with tumor specificity were desired. To construct these functional MSNs, the classic rotaxane structure formed between alkoxysilane tether and α-cyclodextrin (α-CD) was employed to anchor onto the orifices of MSNs as gatekeeper in this work. After subsequent modification by multifunctional peptide (azido-GFLGR7RGDS with tumor-targeting, membrane-penetrating, and cathepsin B-responsive functions) to stabilize the gatekeeper, the resulting functional MSNs showed a strong ability to load and seal DOX in their nanopores. When incubating these DOX-loaded MSNs with tumor and normal cells, the nanoparticles could efficiently employ their surface-encoded RGDS and continuous seven arginine (R7) sequences to target tumor cells, penetrate the cell membrane, and enter tumor cells. Because cathepsin B overexpressed in late endosomes and lysosomes of tumor cells could specifically hydrolyze GFLG sequences of the nanovalves, the DOX-loaded MSNs showed an “off-on” drug release behavior that ∼80% loaded DOX could be released within 24 h and thus showed a high rate of apoptosis. Furthermore, in vitro cellular experiments indicated that DOX-loaded MSNs (DOX@MSN-GFLGR7RGDS/α-CD) had high growth inhibition toward αvβ3-positive HeLa cancerous cells. The research might offer a practical way for designing the tumor-targeted and enzyme-induced drug delivery system for cancer therapy.Keywords: enzyme-sensitive; mesoporous silica nanoparticle; peptide; rotaxane; targeted drug delivery;

A new multi-functional amphiphilic fusion (MFAF) peptide comprised of a multi-functional fusion peptide sequence (GFLGR8GDS) and a hydrophobic polycaprolactone (PCL) tail was designed and prepared. In aqueous solution, through the strong hydrophobic interaction among the PCL tails, this MFAF peptide can self-assemble into core–shell micelles at a low concentration with the anti-tumor drug doxorubicin (DOX) loaded in the core and the multi-functional fusion peptide sequence located on the shell. When incubating the DOX-loaded micelles with tumor and normal cells, the micelles can use the RGD and membrane-penetrating peptide (eight continuous arginine residues, R8) sequences to target tumor cells and penetrate cell membranes. Subsequently, cathepsin B, an enzyme over-expressed in late endosomes and lysosomes of tumor cells that can specifically hydrolyze the GFLG sequence, can break the micellar structure and lead to a rapid release and escape of loaded DOX from endosomes, resulting in the apoptosis of tumor cells. The MFAF peptide presents great potential as a new drug delivery platform for targeted cancer chemotherapy.

In this paper, biodegradable polycations based on polycarbonates with grafted polyethylenimine (PEI) were synthesized as a nonviral vector for gene delivery. Immobilized porcine pancreas lipase (IPPL) was employed to perform the copolymerization of 5-methyl-5-allyloxy carbonyl-trimethylenecarbonate (MAC) with 5,5-dimethyl-trimethylene carbonate (DTC). The DTC molar percent X was equal to 6.7, 12.5, and 45.4, respectively. The resulting copolymers with different compositions (P(MAC-co-DTCx) underwent additional allyl epoxidation and thereby grafted by low molecular weight PEI1800. The MWs of P(MAC-co-DTCx)-g-PEI, measured by GPC-MALLS, were 219800, 179100, and 51700 g/mol with polydispersities of 1.5, 1.4, and 1.2, respectively. Physicochemical properties of these vectors were characterized and the DNA loading was evaluated. P(MAC-co-DTCx)-g-PEI could form nanosized particles (less than 100 nm) with pDNA. The three P(MAC-co-DTCx)-g-PEI/DNA polyplexes had similar buffer capabilities that were better than that of PEI25K and PMAC-g-PEI. Despite a slightly lower DNA binding ability, the PEI-grafted polycarbonates, especially P(MAC-co-DTC45.4)-g-PEI, presented apparently low cytotoxicity and much higher gene transfection efficiency in comparison with PEI25K in 293T cells. Moreover, preincubation of P(MAC-co-DTC6.7)-g-PEI showed a quickly weakening DNA binding capacity, while a suitable degradation rate of vectors would facilitate the efficient release of pDNA from polyplexes after cellular uptake and also reduce cell cytotoxicity. The results of this study demonstrated the promise of P(MAC-co-DTCx)-g-PEI copolymers for efficient gene delivery.

•Four kinds of mercaptan acids modified amphiphilic copolymers were synthesized.•All copolymers could self-assemble into negatively-charged nanomicelles.•The micelles showed high stability, good blood compatibility and low cytotoxicity.•DOX was efficiently loaded by synergetic hydrophobic and electrostatic interaction.•pH-responsive DOX-loaded micelles showed efficient cell uptake and cytotoxicity.In this paper, four different kinds of mercaptan acids modified amphiphilic copolymers mPEG-b-PATMC-g-SRCOOH (R = CH2, CH2CH2, (CH2)10 and CH(COOH)CH2) were successfully synthesized by thiol-ene “click” reaction between pendent carbon-carbon double bonds of PEG-b-PATMC and thiol groups of thioglycolic acid, 3-mercaptopropionic acid, 11-mercaptoundecanoic acid or 2-mercaptosuccinic acid. DLS and TEM measurements showed that all the mPEG-b-PATMC-g-SRCOOH copolymers could self-assemble to form micelles which dispersed in spherical shape with nano-size before and after DOX loading. The positively-charged DOX could effectively load into copolymer micelles via synergistic hydrophobic and electrostatic interactions. All DOX-loaded mPEG-b-PATMC-g-SRCOOH micelles displayed sustained drug release behavior without an initial burst which could be further adjusted by the conditions of ionic strength and pH. Especially in the case of mPEG-b-PATMC-g-S(CH2)10COOH (P3) micelles, the suitable hydrophobility and charge density were not only beneficial to improve the DOX-loading efficiency, they were also good for obtaining smaller particle size, higher micelle stability and more timely drug delivery. Confocal laser scanning microscopy (CLSM) and MTT assays further demonstrated efficient cellular uptake of DOX delivered by mPEG-b-PATMC-g-SRCOOH micelles and potent cytotoxic activity against cancer cells.Illustration of drug-loaded mPEG-b-PATMC-g-SRCOOH micelles via synergistic hydrophobic and electrostatic interactions for efficient loading and release of doxorubicin.