Modulation of macrophage polarity with carboxymethyl chitin gated hollow mesoporous silica nanoparticles for elevating anti-tumor chemotherapy.

The weak immunity of tumors after chemotherapy could cause tumor metastasis and progression. Therefore, to overcome the dilemma of obvious immune deficiency caused by chemotherapy, a nanosystem (N-IL-12/DOX/α-TOS) consisted of thioketal (TK) bonds linked-hollow mesoporous silica nanoparticles (HMSNs) coated with carboxymethyl chitin (CMCH) by electrostatic interaction, and surface-functionalized glucose-regulated protein 78 binding peptide was prepared for loading doxorubicin (DOX), IL-12 and α-tocopheryl succinate (α-TOS). N-IL-12/DOX/α-TOS displayed a mean size of 275 nm after encapsulated DOX, IL-12 and α-TOS with loading contents of 2.04 × 10-4, 4.01 × 10-2 and 7.12 × 10-2, respectively. The drug-free nanoparticles (NPs) showed good biocompatibility to both 4 T1 cells and RAW264.7 macrophages. N-IL-12/DOX/α-TOS could achieve localized release of IL-12, DOX and α-TOS by pH and H2O2 trigger in the tumor microenvironment (TME). Moreover, the combined therapy by N-IL-12/DOX/α-TOS remarkably elevated the anti-tumor therapeutic efficacy, enhanced immune responses via promoting tumor-associated macrophage (TAM) polarization into tumoricidal M1 phenotypes, and decreased lung metastasis with reduced side effects. N-IL-12/DOX/α-TOS exhibited as a promising strategy for combining chemotherapy and local macrophage modulation-immunotherapy for anti-tumor therapy.

Multi-functional carboxymethyl chitin-based nanoparticles for modulation of tumor-associated macrophage polarity.

Current challenge of using cytokines is its poor distribution and systemic side effects. To avoid this issue, we prepared the tumor-targeted and microenvironment-responsive nanocarriers (TRN), which were consisted of α-tocopheryl succinate (α-TOS) loaded mesoporous silica nanoparticles as cores, and surface-modified by thioketal-linkage, electrostatically coated with carboxymethyl chitin, and further anchored glucose-regulated protein 78-binding peptide as shells for encapsulating IL-12. TRN showed a size of 260 nm after encapsulated IL-12 and α-TOS with loading content of 0.0206% and 7.21%, respectively, and exhibited good biocompatibility to 4 T1 cells and macrophages. Moreover, IL-12/α-TOS loaded TRN displayed obvious anti-tumor efficacy on BALB/c nude mice bearing 4 T1 tumors, which was derived from promoted targeting to tumor tissue, endocytosed by macrophages and locally release IL-12 to subsequently repolarize tumor-associated macrophages into tumoricidal M1 phenotype with reduced side effects. The nanosystem exhibited as a promising strategy with functional conversion of macrophages in tumor microenvironment for anti-tumor therapy.