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Biomaterials. 2014 Dec;35(37):9912-9919. doi: 10.1016/j.biomaterials.2014.08.029. Epub 2014 Sep 17.

A self-assembled polymeric micellar immunomodulator for cancer treatment based on cationic amphiphilic polymers.

Author information

1
Department of Biotechnology, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi do 420-743, Republic of Korea.
2
Department of Biomedical Engineering, Yale University, 55 Prospect St., New Haven, CT 06511, USA.
3
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.
4
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.

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.

KEYWORDS:

Antitumor immune responses; Cancer; Cationic polymer; Necrosis; Self-assembly

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