title: A self-assembled polymeric micellar immunomodulator for cancer treatment based on cationic amphiphilic polymers.
abstract: Here, we report a self-assembled polymeric micellar immunomodulator (SPI) for enhanced cancer treatment based on cationic amphiphilic polymers. To obtain the cationic amphiphilic polymer, the hydrophobic all-trans-retinoic acid (ATRA) was conjugated with a hydrophilic low-molecular-weight PEI (LowPEI, Mn = 1.8 kDa). The ATRA-LowPEI conjugates could self-assemble in aqueous media, forming micelles with a strong positive charge (∼+40 mV) and particle sizes of ~70 nm. Compared to conventional therapeutic agents (e.g., cisplatin), the SPI exhibited enhanced anti-cancer activity regardless of drug resistance. After mechanistic in vitro cell death studies, we revealed that the mechanical disruptive force generated by the cationic charge of SPI primarily induced necrotic cell death. Furthermore, the organelle fragments induced by the necrotic cell death triggered antitumoral immune responses. Therefore, SPI induced synergistic effects of the cationic charge-induced necrosis and antitumoral immune responses could produce an effective cancer treatment. In addition, the SPI was shielded by hyaluronic acid (HA/SPI complex) to enhance its tumor selectivity in vivo. Finally, the HA/SPI complex accumulated selectively into tumor sites after systemic administration into tumor-bearing mice, exhibiting effective antitumoral effects without systemic toxicity. Therefore, this technology holds great potential for translation into a clinical cancer treatment.
authors.affiliation: Department of Biotechnology, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi do 420-743, Republic of Korea.
authors.forename: Hyeona
authors.initials: H
authors.lastname: Yim
authors.affiliation: Department of Biotechnology, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi do 420-743, Republic of Korea.
authors.forename: Wooram
authors.initials: W
authors.lastname: Park
authors.affiliation: Department of Biomedical Engineering, Yale University, 55 Prospect St., New Haven, CT 06511, USA.
authors.forename: Dongin
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Biomedical Engineering, Yale University, 55 Prospect St., New Haven, CT 06511, USA; Department of Chemical and Biomedical Engineering, Yale University, 55 Prospect St., New Haven, CT 06511, USA.
authors.forename: Tarek M
authors.initials: TM
authors.lastname: Fahmy
authors.affiliation: Department of Biotechnology, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi do 420-743, Republic of Korea. Electronic address: kna6997@catholic.ac.kr.
authors.forename: Kun
authors.initials: K
authors.lastname: Na
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use*; D002412:Cations / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000032:analysis / Q000276:immunology; D007155:Immunologic Factors / Q000737:chemistry / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology; D011094:Polyethyleneimine / Q000737:chemistry / Q000627:therapeutic use*; D013501:Surface-Active Agents / Q000737:chemistry / Q000627:therapeutic use; D014212:Tretinoin / Q000737:chemistry / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D002412:Cations; D016207:Cytokines; D007155:Immunologic Factors; D008823:Micelles; D013501:Surface-Active Agents; D014212:Tretinoin; D011094:Polyethyleneimine
keywords: Antitumor immune responses; Cancer; Cationic polymer; Necrosis; Self-assembly