Recommended Citation
Meng, Fanfei; Wang, Jianping; He, Yanying; Cresswell, Gregory M.; Lanman, Nadia A.; Lyle, L. Tiffany; Ratliff, Timothy L.; and Yeo, Yoon, "A single local delivery of paclitaxel and nucleic acids via an immunoactive polymer eliminates tumors and induces antitumor immunity" (2022). Purdue University Libraries Open Access Publishing Fund. Paper 164.
http://dx.doi.org/10.1073/pnas.2122595119
DOI
10.1073/pnas.2122595119
Date of this Version
5-24-2022
Keywords
polyethyleneimine-lithocholic acid conjugate, immunoactive carrier, immunogenic cell death inducer, nucleic acids/nucleotides, local immunotherapy
Abstract
Despite recent advances in cancer therapy, hard-to-reach, unidentified tumors remain a significant clinical challenge. A promising approach is to treat locatable and accessible tumors locally and stimulate antitumor immunity in situ to exert systemic effects against distant tumors. We hypothesize that a carrier of immunotherapeutics can play a critical role in activating antitumor immunity as an immunoadjuvant and a local retainer of drug combinations. Here, we develop a polyethyleneimine-lithocholic acid conjugate (2E′), which forms a hydrophobic core and cationic surface to codeliver hydrophobic small molecules and anionic nucleic acids and activates antigen-presenting cells via the intrinsic activities of 2E′ components. 2E′ delivers paclitaxel and small-interfering RNA (siRNA) targeting PD-L1 (or cyclic dinucleotide, [CDN]) to induce the immunogenic death of tumor cells and maintain the immunoactive tumor microenvironment, and further activates dendritic cells and macrophages, leveraging the activities of loaded drugs. A single local administration of 2E′ or its combination with paclitaxel and PD-L1–targeting siRNA or CDN induces strong antitumor immunity, resulting in immediate regression of large established tumors, tumor-free survival, an abscopal effect on distant tumors, and resistance to rechallenge and metastasis in multiple models of murine tumors, including CT26 colon carcinoma, B16F10 melanoma, and 4T1 breast cancer. This study supports the finding that local administration of immunotherapeutics, when accompanied by the rationally designed carrier, can effectively protect the host from distant and recurrent diseases.
Comments
This is the publisher PDF of F. Meng, J. Wang, Y. He, G.M. Cresswell, N.A. Lanman, L.T. Lyle, T.L. Ratliff, Y. Yeo, A single local delivery of paclitaxel and nucleic acids via an immunoactive polymer eliminates tumors and induces antitumor immunity, PNAS 119 (22) e2122595119, 2022. This article is distributed under a CC-BY license, and is available at DOI: 10.1073/pnas.2122595119.