A single-shot prophylactic tumor vaccine enabled by an injectable biomembrane hydrogel.

Prophylactic tumor vaccines hold great promise against tumor occurrence. However, their clinical efficacy remains low due to inadequate activation of strong-sustainable immunity. Herein, a biomembrane hydrogel was designed as a powerful single-shot prophylactic tumor vaccine. Mannose-decorated hybrid biomembrane (MHCM) modified with oxidized sodium alginate (OSA) was designed as a gelator (O-MHCM), where the hybrid biomembrane (HCM) is a hybridization of bacterial outer membrane vesicles (OMV) and tumor cell membranes (TCM). The O-MHCM enables quick gelation subcutaneously where the cysteine protease inhibitor E64 is encapsulated in hydrogel micropores. After a single vaccination of E64@O-MHCM hydrogel, MHCM and E64 are released sustainably due to OSA moiety degradation. The MHCM enables active targeting to dendritic cells (DC) and effective DC maturation. Meanwhile, the E64 enables sufficient antigen availability for subsequent cross presentation. Ultimately, strong and sustainable T lymphocyte-mediated immunity was elicited, demonstrating a strong prophylactic effect against breast tumors. This study provides a long-lasting platform to prevent tumor occurrence, opening an innovative avenue for the design of a single-shot prophylactic tumor vaccine. STATEMENT OF SIGNIFICANCE: Developing a single-shot prophylactic tumor vaccine to elicit strong-sustainable immunity is of great interest clinically. Here, a prophylactic tumor vaccine was designed using an injectable biomembrane hydrogel for achieving strong-sustainable immunity. The mannose-tailored hybrid biomembrane was modified with oxidized sodium alginate to result in a gelator, which enabled the formation of the hydrogel after subcutaneous injection. Cysteine protease inhibitor E64 was incorporated into the micropores of the hydrogel. The hydrogel induced strong-sustainable immunity through the continuous release of active components. This was facilitated by the mannose moiety, which enabled active targeting, as well as the antigen and adjuvant function of biomembrane, and the E64-enabled suppression of antigen degradation. The biomembrane hydrogel demonstrated powerful prevention of 4T1 breast tumors. This study offers an attractive strategy for designing a single-shot prophylactic tumor vaccine.

Co-delivery of docetaxel and chloroquine via PEO-PPO-PCL/TPGS micelles for overcoming multidrug resistance.

The combination of two or more drug is a promising strategy to suppress the multidrug resistance (MDR) through different action mechanisms. Co-delivery drugs via polymeric micelle can minimize the amount of each drug and reduce toxic side effects. Here we co-encapsulate anticancer drug docetaxel (DTX) and autophagy inhibitor chloroquine (CQ) in complex micelles based on poly(ethylene oxide)-block-poly(propylene oxide)-block-poly(ϵ-caprolactone) (PEO-PPO-PCL) and D-α-tocopheryl poly(ethylene glycol) (TPGS) for enhancing anticancer effects. Two series copolymer with different length of hydrophobic chain were synthesized (PEO68-PPO34-PCL18 and PEO68-PPO34-PCL36) in our lab. The dual-drug micelles possessed nanosize and sustained release profile in vitro. Drug-loaded micelles have low hemolysis rate (<5%), indicating that they are safe for use in vivo. Studies on cellular uptake demonstrate that the micelles can effectively accumulate in cancer cells. Furthermore, in vitro cytotoxicity with different DTX/CQ mass ratio are studied and the sample with a DTX/CQ ratio of 0.8/0.2 is found to have the strongest synergism effect. The co-delivery micelles have obviously higher therapeutic effects against MCF-7 and MCF-7/ADR cells than either free drug or individually DTX-loaded micelles. The IC50 values of DTX/CQ-loaded PEO68-PPO34-PCL18/TPGS and PEO68-PPO34-PCL36/TPGS micelles are 134.16 and 194.74 fold smaller than that of free DTX after 48 h treatment with MCF-7/ADR cells, respectively. Therefore, the as-prepared co-delivery of DTX and CQ based on PEO-PPO-PCL/TPGS micelles can provide a promising combined therapeutic strategy for enhanced antitumor therapy.

Catanionic drug-derivative nano-objects constructed by chlorambucil and its derivative for efficient leukaemia therapy.

A new carrier-free catanionic drug-derivative nano-object strategy is developed for leukaemia therapy. The as-prepared drug-derivative nano-objects are formed by ionic pairs of hydrophobic anticancer drug chlorambucil (CLB) and its derivative N-(2-Amino-ethyl)-4-{4-[bis-(2-chloro-ethyl)-amino]-phenyl}-butyramide (CLBM). The designed drug delivery system has the advantage of 100% drug content without additional carrier materials. The ionic pairs are formed by proton exchange between CLB and CLBM. Due to the amphiphilicity of the ionic pairs, they can assemble into well-defined drug-derivative (CLB-CLBM) nano-objects. Series of techniques such as transmission electron microscopy (TEM), dynamic light scattering (DLS) and electrical conductivity are used to investigate the property of the solution and aggregation behaviour of as-prepared drug-derivative ionic pairs. In vitro drug release study of the as-prepared nano-objects shows their prolonged drug release behavior. Specifically, in vitro cytotoxicity results of these nano-objects show obviously higher cytotoxicity, which is promising for clinical efficacy. This study may pave the way for the fabrication of carrier-free drug delivery system with efficient cancer therapy.

Docetaxel-loaded PEO-PPO-PCL/TPGS mixed micelles for overcoming multidrug resistance and enhancing antitumor efficacy.

There are two major hurdles for the current anti-cancer drug delivery systems. One is the emergence of multidrug resistance (MDR) and the other is the conflict between long-circulation and cellular uptake. In the present study, the anticancer drug docetaxel (DTX) was successfully loaded into three series of micelles via self-assembly using a mixture of PEO-PPO-PCL and d-α-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS), for the purpose of prolonging the blood circulation time as well as overcoming MDR of DTX. Three series of copolymers with different PCL molecular weights, PEO68-PPO34-PCL9, PEO68-PPO34-PCL18 and PEO68-PPO34-PCL36, were synthesized. The prepared spherical mixed micelles (MM) were found to possess nanoscale size (25-135 nm). The PEO-PPO-PCL/TPGS mixed micelles had a low critical micelle concentration (∼10-6 g mL-1) and a low hemolysis rate (<5%), which has proved that they are safe for use in vivo. Moreover, they had obvious sustained release behavior in vitro and a longer circulation time than free DTX in vivo. The P-gp inhibition assay, cellular uptake and MTT assay in cancer cells exhibited that DTX-loaded MM could overcome MDR, show higher cellular uptake and higher antitumor efficacy than free DTX. The IC50 values demonstrated that the three series of DTX-loaded MM were 69, 82 and 100 fold effective than free DTX after 72 h treatment with MCF-7 cells, respectively. Therefore, these results demonstrated that the prepared DTX-loaded MM provide desirable application in cancer chemotherapy.

A review of polypeptide-based polymersomes.

Self-assembled systems from biodegradable amphiphilic polymers at the nanometer scale, such as nanotubes, nanoparticles, polymer micelles, nanogels, and polymersomes, have attracted much attention especially in biomedical fields. Among these nano-aggregates, polymersomes have attracted tremendous interests as versatile carriers due to their colloidal stability, tunable membrane properties and ability of encapsulating or integrating a broad range of drugs and molecules. Biodegradable block polymers, especially aliphatic polyesters such as polylactide, polyglycolide and poly (ε-caprolactone) have been widely used as biomedical materials for a long time to well fit the requirement of biomedical drug carriers. To have a precise control of the aggregation behavior of nano-aggregates, the more ordered polypeptide has been used to self-assemble into the drug carriers. In this review we focus on the study of polymersomes which also named pepsomes formed by polypeptide-based copolymers and attempt to clarify the polypeptide-based polymersomes from following aspects: synthesis and characterization of the polypeptide-based copolymers, preparation, multifunction and application of polypeptide-based polymersomes.