Dendronized polymer conjugates with amplified immunogenic cell death for oncolytic immunotherapy

Yachao Li; Lian Li; Jiawei Wang; D Christopher Radford; Zhongwei Gu; Jindřich Kopeček; Jiyuan Yang

doi:10.1016/j.jconrel.2020.10.041

Dendronized polymer conjugates with amplified immunogenic cell death for oncolytic immunotherapy

J Control Release. 2021 Jan 10:329:1129-1138. doi: 10.1016/j.jconrel.2020.10.041. Epub 2020 Oct 21.

Authors

Yachao Li¹, Lian Li², Jiawei Wang², D Christopher Radford³, Zhongwei Gu⁴, Jindřich Kopeček⁵, Jiyuan Yang⁶

Affiliations

¹ Department of Pharmaceutics and Pharmaceutical Chemistry, Center for Controlled Chemical Delivery, University of Utah, Salt Lake City, UT 84112, United States; National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, Sichuan 610064, PR China.
² Department of Pharmaceutics and Pharmaceutical Chemistry, Center for Controlled Chemical Delivery, University of Utah, Salt Lake City, UT 84112, United States.
³ Department of Biomedical Engineering, University of Utah, Salt Lake City, UT 84112, United States.
⁴ National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, Sichuan 610064, PR China.
⁵ Department of Pharmaceutics and Pharmaceutical Chemistry, Center for Controlled Chemical Delivery, University of Utah, Salt Lake City, UT 84112, United States; Department of Biomedical Engineering, University of Utah, Salt Lake City, UT 84112, United States. Electronic address: [email protected].
⁶ Department of Pharmaceutics and Pharmaceutical Chemistry, Center for Controlled Chemical Delivery, University of Utah, Salt Lake City, UT 84112, United States. Electronic address: [email protected].

PMID: 33098912
DOI: 10.1016/j.jconrel.2020.10.041

Abstract

The architecture of multivalent polymers exerts an amplified interaction between attached ligands and targets. In current research, we reveal that a dendronized polymer augments the efficacy of an oncolytic peptide (OP; KKWWKKWDipK) for immunotherapy by exploiting (i) "flexible" linear polymer backbone to facilitate interactions with biomembrane systems, and (ii) "rigid" dendronized side chains to enhance the membrane lytic property. We show that a dendronized N-(2-hydroxypropyl)methacrylamide (HPMA) polymer-OP conjugate (PDOP) adopts α-helix secondary structure and induces robust immunogenic cell death (ICD) in cancer cells as characterized by multiple damage-associated molecular patterns (DAMPs) which include intracellular formation of reactive oxygen species (ROS) and surface exposure of calreticulin (CRT). These events convert immunosuppressive 4T1 tumor to an immunoresponsive one by recruiting CD8+ cytotoxic T cells into tumor beds. Combination of PDOP with anti-PD-L1 immune checkpoint blockade (ICB) increases the number of effector memory T cells and completely eradicates 4T1 tumors in mice. Our findings suggest that PDOP is a promising platform for oncolytic immunotherapy.

Keywords: Dendronized polymer; HPMA; Immunogenic cell death; Oncolytic immunotherapy; PD-L1 blockade; Tumor immune microenvironment.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Immunogenic Cell Death*
Immunotherapy
Mice
Neoplasms* / therapy
Polymers
T-Lymphocytes, Cytotoxic

Substances

Polymers