Tumor associated macrophage-targeted microRNA delivery with dual-responsive polypeptide nanovectors for anti-cancer therapy

• Published in: Biomaterials 2017-07, Vol.134, p.166-179
• Main Authors: Liu, Lanlan, Yi, Huqiang, He, Huamei, Pan, Hong, Cai, Lintao, Ma, Yifan
• Format: Article
• Language: English
• Subjects: Advanced Basic Science; Animals; Cancer therapy; Dentistry; Electrophoresis, Agar Gel; Female; Interleukin-12 - metabolism; Killer Cells, Natural - metabolism; Magnetic Resonance Spectroscopy; Melanoma - metabolism; Melanoma - therapy; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mice, Nude; MicroRNAs - genetics; MicroRNAs - physiology; miR155; Nanoparticles; Nanoparticles - chemistry; Nitric Oxide Synthase Type II - metabolism; Peptides - chemistry; RAW 264.7 Cells; Signal Transduction - genetics; Signal Transduction - physiology; T-Lymphocytes - metabolism; Targeted delivery; Tumor-associated macrophages
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2017.04.043

Abstract Repolarizing Tumor-associated macrophages (TAMs) to anti-tumor M1 macrophages with microRNA (miR) is a plausible approach for cancer treatment. However, how to achieve TAM-targeted miR delivery remains a challenge. The present study generated redox/pH dual-responsive hybrid polypeptide nanovectors, which consisted of self-crosslinked redox-responsive nanoparticles based on galactose-functionalized n-butylamine-poly(L-lysine)- b-poly(L-cysteine) polypeptides (GLC) coated with DCA-grafted sheddable PEG-PLL (sPEG) copolymers. The ex vivo study showed that sPEG shielded cationic GLC core at physiological pH but quickly shed off to re-expose GLC due to it charge reversible property. Encapsulation with sPEG/GLC nanovectors effectively facilitated macrophage-targeted miR delivery at the acidic condition but diminished miR uptake at neutral pH. Administration of miR155-loaded sPEG/GLC (sPEG/GLC/155) nanocomplexes increased miR155 expression in TAMs about 100–400 folds both in vitro and in vivo . sPEG/GLC/155 also effectively repolarized immunosuppressive TAMs to anti-tumor M1 macrophages through elevating M1 macrophage markers (IL-12, iNOS, MHC II) and suppressing M2 macrophage markers (Msr2 and Arg1) in TAMs. Moreover, the treatment of sPEG/GLC/155 significantly increased activated T lymphocytes and NK cells in tumors, which consequently led to robust tumor regression. Hence, TAM-targeted delivery of miR with redox/pH dual-responsive sPEG/GLC nanovectors could be a promising approach to re-polarize TAMs to M1 macrophages in situ and induce tumor regression.