Co-delivery of Doxorubicin and Interferon‑γ by Thermosensitive Nanoparticles for Cancer Immunochemotherapy

A dual-sensitive nanoparticle delivery system was constructed by incorporating an acid sensitive hydrazone linker into thermosensitive nanoparticles (TSNs) for co-encapsulating doxorubicin (DOX) and interferon γ (IFNγ) and to realize the co-delivery of chemotherapy and immunotherapy agents against melanoma. DOX, a chemotherapeutic drug, was conjugated to TSNs by a pH-sensitive chemical bond, and IFNγ, a potent immune-modulator, was absorbed into TSNs through the thermosensitivity and electrostatics of nanoparticles. Consequently, the dual sensitive drug-loaded TSN delivery systems were successfully built and showed an obvious core–shell structure, good encapsulation efficiency of drugs, sustained and sensitive drug release, prolonged circulation time, as well as excellent synergistic antitumor efficiency against B16F10 tumor bearing mice. Moreover, the combinational antitumor immune responses of hydrazone bearing DOX/IFNγ-TSN (hyd) were strengthened by activating Th1-type CD4⁺ T cells, cytotoxic T lymphocytes, and natural killer cells, downregulating the expression levels of immunosuppressive cytokines, such as IL10 and TGFβ, and upregulating the secretion of IL2 and TNFα. Taken together, the multifunctional TSNs system provides a promising strategy for multiple drugs co-delivery with distinct properties

Nitric Oxide Releasing d‑α-Tocopheryl Polyethylene Glycol Succinate for Enhancing Antitumor Activity of Doxorubicin

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 <i>t</i>_1/2, 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

Erythrocyte Membrane-Enveloped Polymeric Nanoparticles as Nanovaccine for Induction of Antitumor Immunity against Melanoma

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-<i>co</i>-glycolide) (PLGA) nanoparticles for antigenic peptide (hgp100_25–33) 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 <i>in vitro</i> 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

Tumor Microenvironment Responsive Nanogel for the Combinatorial Antitumor Effect of Chemotherapy and Immunotherapy

A biomimetic nanogel with tumor microenvironment responsive property is developed for the combinatorial antitumor effects of chemotherapy and immunotherapy. Nanogels are formulated with hydroxypropyl-β-cyclodextrin acrylate and two opposite charged chitosan derivatives for entrapping anticancer drug paclitaxel and precisely controlling the pH responsive capability, respectively. The nanogel supported erythrocyte membrane can achieve “nanosponge” property for delivering immunotherapeutic agent interleukin-2 without reducing the bioactivity. By responsively releasing drugs in tumor microenvironment, the nanogels significantly enhanced antitumor activity with improved drug penetration, induction of calreticulin exposure, and increased antitumor immunity. The tumor microenvironment is remodeled by the combination of these drugs in low dosage, as evidenced by the promoted infiltration of immune effector cells and reduction of immunosuppressive factors