title: Effective melanoma immunotherapy with interleukin-2 delivered by a novel polymeric nanoparticle.
abstract: Interleukin-2 (IL-2) has been shown to possess antitumor activity in numerous preclinical and clinical studies. However, the short half-life of recombinant IL-2 protein in serum requires repeated high-dose injections, resulting in severe side effects. Although adenovirus-mediated IL-2 gene therapy has shown antitumor efficacy, the host antibody response to adenoviral particles and potential biosafety concerns still obstruct its clinical applications. Here we report a novel nanopolymer for IL-2 delivery, consisting of low molecular weight polyethylenimine (600 Da) linked by β-cyclodextrin and conjugated with folate (named H1). H1 was mixed with IL-2 plasmid to form H1/pIL-2 polyplexes of around 100 nm in diameter. Peritumoral injection of these polyplexes suppressed the tumor growth and prolonged the survival of C57/BL6 mice bearing B16-F1 melanoma grafts. Importantly, the antitumor effects of H1/pIL-2 (50 μg DNA) were similar to those of recombinant adenoviruses expressing IL-2 (rAdv-IL-2; 2 × 10(8) pfu). Furthermore, we showed that H1/pIL-2 stimulated the activation and proliferation of CD8+, CD4+ T cell, and natural killer cells in peripheral blood and increased the infiltration of CD8+, CD4+ Tcells, and natural killer cells into the tumor environment. In conclusion, these results show that H1/pIL-2 is an effective and safe melanoma therapeutic with an efficacy comparable to that of rAdv-IL-2. This treatment represents an alternative gene therapy strategy for melanoma.
authors.affiliation: Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yao
authors.forename: Samuel S
authors.initials: SS
authors.lastname: Ng
authors.forename: Long-Fei
authors.initials: LF
authors.lastname: Huo
authors.forename: Billy K C
authors.initials: BK
authors.lastname: Chow
authors.forename: Zan
authors.initials: Z
authors.lastname: Shen
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.forename: Johnny
authors.initials: J
authors.lastname: Sze
authors.forename: Otis
authors.initials: O
authors.lastname: Ko
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.forename: Alexander
authors.initials: A
authors.lastname: Yue
authors.forename: Li-Wei
authors.initials: LW
authors.lastname: Lu
authors.forename: Xiu-Wu
authors.initials: XW
authors.lastname: Bian
authors.forename: Hsiang-Fu
authors.initials: HF
authors.lastname: Kung
authors.forename: Marie C
authors.initials: MC
authors.lastname: Lin
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D005260:Female; D005492:Folic Acid / Q000737:chemistry; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics; D007694:Killer Cells, Natural / Q000378:metabolism; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D011094:Polyethyleneimine / Q000737:chemistry; D011108:Polymers / Q000737:chemistry / Q000627:therapeutic use; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism; D019076:Transgenes; D047392:beta-Cyclodextrins / Q000737:chemistry
chemical_list: D007376:Interleukin-2; D011108:Polymers; D047392:beta-Cyclodextrins; D011094:Polyethyleneimine; D005492:Folic Acid; C031215:betadex