Cancer immunotherapy is mainly focused on manipulating patient's own immune system to recognize and destroy cancer cells. Vaccine formulations based on nanotechnology have been developed to target delivery antigens to antigen presenting cells (APCs), especially dendritic cells (DCs) for efficiently induction of antigen-specific T cells response. To enhance DC targeting and antigen presenting efficiency, we developed erythrocyte membrane-enveloped poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles for antigenic peptide (hgp10025-33) and toll-like receptor 4 agonist, monophosphoryl lipid (MPLA). A Mannose-inserted membrane structure was constructed to actively target APCs in the lymphatic organ, and redox-sensitive peptide-conjugated PLGA nanoparticles were fabricated which prone to cleave in the intracellular milieu. The nanovaccine demonstrated the retained protein content in erythrocyte and enhanced in vitro cell uptake. An antigen-depot effect was observed in the administration site with promoted retention in draining lymph nodes. Compared with other formulations after intradermal injection, the nanovaccine prolonged tumor-occurring time, inhibited tumor growth, and suppressed tumor metastasis in prophylactic, therapeutic, and metastatic melanoma models, respectively. Additionally, we revealed that nanovaccine effectively enhanced IFN-γ secretion and CD8(+) T cell response. Taken together, these results demonstrated the great potential in applying an erythrocyte membrane-enveloped polymeric nanoplatform for an antigen delivery system in cancer immunotherapy.

To overcome the multidrug resistance (MDR) of P-glycoprotein (P-gp) substrate anticancer drugs, such as paclitaxel (PTX), a novel dual-functional prodrug, D-α-tocopherol polyethylene glycol succinate (TPGS) based PTX prodrug (TPGS-S-S-PTX), was synthesized here to fulfill the synergistic effect of P-gp inhibiting and intracellular redox-sensitive release. The prodrug could self-assemble into stable micelles in physiological environment with a diameter of ∼140 nm, while it disassociated in reductive condition and released PTX and TPGS active derivatives rapidly. High cell cytotoxicity in PTX-resistant human ovarian cell line A2780/T was observed with enhanced PTX accumulation due to the P-gp inhibition by the TPGS moiety. The IC50 of TPGS-S-S-PTX was 55% and 91% more effective than that of Taxol (clinical formulation of PTX) and uncleavable TPGS-C-C-PTX prodrug, respectively. This was found to be related with the increased apoptosis/necrosis and cell arrest in G2/M phase. In vivo evaluation of the TPGS-S-S-PTX prodrug exhibited an extended half-life, increased AUC (area under the concentration-time curve), enhanced tumor distribution and significant tumor growth inhibition with reduced side effects as compared to Taxol and TPGS-C-C-PTX. This prodrug has great potential in improving efficiency in the treatment of MDR tumors.

Nitric oxide (NO) has attracted much attention for its antitumor activity and synergistic effects when codelivered with anticancer agents. However, due to its chemical instability and short half-life, delivering gaseous NO directly to tumors is still challenging. Herein, we synthesized a NO releasing polymer, nitrate functionalized d-α-tocopheryl polyethylene glycol succinate (TNO3). TNO3 was able to self-assemble into stable micelles in physiological conditions, accumulate in tumors, and release ∼90% of NO content in cancer cells for 96 h. It further exhibited significant cancer cell cytotoxicity and apoptosis compared with nitroglycerine (GTN). Notably, TNO3 could also serve as an enhancer for the common chemotherapeutic drug doxorubicin (DOX). Codelivering TNO3 with DOX to hepatocarcinoma HepG2 cancer cells strengthened the cellular uptake of DOX and enabled the synergistic effect between NO and DOX to induce higher cytotoxicity (∼6.25-fold lower IC50). Moreover, for DOX-based chemotherapy in tumor-bearing mice, coadministration with TNO3 significantly extended the blood circulation time of DOX (14.7-fold t1/2, 6.5-fold mean residence time (MRT), and 13.7-fold area under curve (AUC)) and enhanced its tumor accumulation and penetration, thus resulting in better antitumor efficacy. In summary, this new NO donor, TNO3, may provide a simple but effective strategy to enhance the therapeutic efficacy of chemotherapeutic drugs.

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