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Co-delivery of IL-12 cytokine gene and cisplatin prodrug by a polymetformin-conjugated nanosystem for lung cancer chemo-gene treatment through chemotherapy sensitization and tumor microenvironment modulation
- Source :
- Acta Biomaterialia. 128:447-461
- Publication Year :
- 2021
- Publisher :
- Elsevier BV, 2021.
-
Abstract
- The combination of chemotherapy and gene therapy has been indicated as a promising approach for cancer therapy. However, this combination strategy is still faced a challenge by the lack of suitable carriers to co-loaded chemotherapeutic drug and gene into one single nanoplatform. In this study, a tumor-targeted HC/pIL-12/polyMET micelleplexes were developed for the co-loading and co-delivery of cisplatin (CDDP) and plasmid encoding interleukin-12 gene (pIL-12), which would be utilized to generate synergistic actions through chemotherapy sensitization and microenvironment modulation. The HC/pIL-12/polyMET exhibited desirable particle size, superior serum stability, effective intracellular CDDP release and pIL-12 transfection efficiency. More important, the HC/pIL-12/polyMET generated the enhanced LLC cell proliferation inhibition and apoptosis induction efficiency. The long-circulating HC/pIL-12/polyMET micelleplexes promoted the accumulation of CDDP and pIL-12 in tumor site, which resulted in significantly inhibiting the growth of lung cancer, and prolonging the overall survival of tumor-bearing mice. The underlying immune mechanism demonstrated the combination of CDDP and pIL-12 activated immune effector cells to release IFN-γ and induced M1-type differentiation of tumor-related macrophages, thereby generating synergistic chemoimmunotherapy effect. Taken together, this study may provide an effective strategy for drug/gene co-delivery and cancer chemoimmunotherapy. STATEMENT OF SIGNIFICANCE: Chemoimmunotherapy has been indicated as an approach to improve efficacy of cancer therapy. Herein, a tumor-targeted micelleplexes (HC/pIL-12/polyMET) were developed for the co-delivery of cisplatin (CDDP) and plasmid encoding IL-12 gene (pIL-12), which can employ the synergistic effects through chemotherapy sensitization and microenvironment modulation. The HC/pIL-12/polyMET exhibited desirable particle size, superior serum stability, high gene transfection efficiency and antitumor activity on tumor cell proliferation inhibition and apoptosis induction. More importantly, the long-circulating HC/pIL-12/polyMET micelleplexes could effectively accumulate in tumor sites and then rapidly release the CDDP and pIL-12, significantly inhibit the growth of lung cancer. This strategy provides a new concept for chemo-gene combination with a strengthened overall therapeutic efficacy of chemoimmunotherapy.
- Subjects :
- Lung Neoplasms
Genetic enhancement
0206 medical engineering
Biomedical Engineering
Antineoplastic Agents
02 engineering and technology
Biochemistry
Biomaterials
Mice
Chemoimmunotherapy
Cell Line, Tumor
Tumor Microenvironment
medicine
Animals
Prodrugs
Lung cancer
Molecular Biology
Sensitization
Cisplatin
Tumor microenvironment
Chemistry
Cancer
General Medicine
Transfection
021001 nanoscience & nanotechnology
medicine.disease
Interleukin-12
020601 biomedical engineering
medicine.anatomical_structure
Cancer research
Cytokines
Nanoparticles
0210 nano-technology
Biotechnology
medicine.drug
Subjects
Details
- ISSN :
- 17427061
- Volume :
- 128
- Database :
- OpenAIRE
- Journal :
- Acta Biomaterialia
- Accession number :
- edsair.doi.dedup.....20eb6bb29a1a3504b190581c8ea0f4d7