Tumor Microenvironment-Triggered Charge Reversal Polymetformin-Based Nanosystem Co-Delivered Doxorubicin and IL-12 Cytokine Gene for Chemo-Gene Combination Therapy on Metastatic Breast Cancer.

Publisher: American Chemical Society Country of Publication: United States NLM ID: 101504991 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1944-8252 (Electronic) Linking ISSN: 19448244 NLM ISO Abbreviation: ACS Appl Mater Interfaces Subsets: MEDLINE

Original Publication: Washington, D.C. : American Chemical Society

Drug Delivery Systems*; Antineoplastic Agents/*pharmacology ; Breast Neoplasms/*therapy ; Doxorubicin/*pharmacology ; Interleukin-12/*genetics ; Metformin/*pharmacology ; Polymers/*pharmacology; Animals ; Antineoplastic Agents/chemical synthesis ; Antineoplastic Agents/chemistry ; Apoptosis/drug effects ; Breast Neoplasms/immunology ; Breast Neoplasms/pathology ; Cell Proliferation/drug effects ; Combined Modality Therapy ; Doxorubicin/chemistry ; Drug Screening Assays, Antitumor ; Female ; Genetic Therapy ; Interleukin-12/immunology ; Mammary Neoplasms, Experimental/immunology ; Mammary Neoplasms, Experimental/pathology ; Mammary Neoplasms, Experimental/therapy ; Metformin/chemical synthesis ; Metformin/chemistry ; Mice ; Mice, Inbred BALB C ; Molecular Structure ; Polymers/chemical synthesis ; Polymers/chemistry ; Tumor Cells, Cultured ; Tumor Microenvironment/drug effects ; Tumor Microenvironment/immunology

Cancer metastasis is the leading cause of high mortality and disease recurrence in breast cancer. In this study, a novel tumor microenvironment charge reversal polymetformin (PMet)-based nanosystem co-delivering doxorubicin (DOX) and plasmid encoding IL-12 gene (pIL-12) was developed for chemo-gene combination therapy on metastatic breast cancer. Cationic PMet was readily self-assembled into micelles for DOX physical encapsulation and pIL-12 complexation, and a hyaluronidase-sensitive thiolated hyaluronic acid (HA-SH) was then collaboratively assembled to the pIL-12/DOX-PMet micelleplexes, abbreviated as HA/pIL-12/DOX-PMet. DOX/pIL-12 loaded in HA/pIL-12/DOX-PMet micelleplexes presented prolonged circulation in blood, efficient accumulation in tumors, and internalization in tumor cells via CD44 receptor-mediated tumor specific-targeting, and DOX/pIL-12 was co-released in endo/lysosomes tumor microenvironment followed by HAase-triggered HA-SH deshielding from HA/pIL-12/DOX-PMet micelleplexes. Moreover, HA/PMet micelleplexes displayed excellent pIL-12 transfection and IL-12 expression in tumors of 4T1 tumor-bearing mice. Importantly, HA/pIL-12/DOX-PMet micelleplexes synergistically enhanced the NK cells and tumor infiltrated cytotoxic T lymphocytes and modulated the polarization from protumor M2 macrophages to activated antitumor M1 macrophages, with concomitant decreasing of the immunosuppressive regulatory T (Treg) cells, accompanied by an increase in the cytokines expression of IL-12, IFN-γ and TNF-α, consequently showing an improved antitumor and antimetastasis activity in 4T1 breast cancer lung metastasis mice model. In conclusion, the tumor microenvironment charge reversal HA/PMet nanosystem holds great promise for DOX/pIL-12 co-delivery and exploitation in chemo-gene combination therapy on metastatic breast cancer.

Keywords: DOX; HA/pIL-12/DOX-PMet; chemo−gene combination therapy; metastatic breast cancer; pIL-12; tumor microenvironment charge reversal

0 (Antineoplastic Agents)
0 (Polymers)
187348-17-0 (Interleukin-12)
80168379AG (Doxorubicin)
9100L32L2N (Metformin)

Date Created: 20200914 Date Completed: 20210310 Latest Revision: 20210310

20240829

10.1021/acsami.0c14405

32924511