One-shot dual gene editing for drug-resistant pancreatic cancer therapy

Eun-Jeong Won; Hyeji Park; Seung-Hee Chang; Jin Hyun Kim; Hojeong Kwon; Young-Seok Cho; Tae-Jong Yoon

doi:10.1016/j.biomaterials.2021.121252

One-shot dual gene editing for drug-resistant pancreatic cancer therapy

Biomaterials. 2021 Dec:279:121252. doi: 10.1016/j.biomaterials.2021.121252. Epub 2021 Nov 12.

Authors

Eun-Jeong Won¹, Hyeji Park², Seung-Hee Chang³, Jin Hyun Kim³, Hojeong Kwon⁴, Young-Seok Cho⁵, Tae-Jong Yoon⁶

Affiliations

¹ Laboratory of Nanopharmacy, College of Pharmacy, Research Institute of Pharmaceutical Science and Technology (RIPST), Ajou University, Suwon, South Korea.
² Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 06591, Seoul, South Korea.
³ Laboratory of Nanopharmacy, College of Pharmacy, Research Institute of Pharmaceutical Science and Technology (RIPST), Ajou University, Suwon, South Korea; Moogene Medi Institute, Korea-Bio Park, Seongnam, South Korea.
⁴ Department of Anthropology, College of Arts and Science, New York University, New York, USA.
⁵ Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 06591, Seoul, South Korea. Electronic address: yscho@catholic.ac.kr.
⁶ Laboratory of Nanopharmacy, College of Pharmacy, Research Institute of Pharmaceutical Science and Technology (RIPST), Ajou University, Suwon, South Korea; Moogene Medi Institute, Korea-Bio Park, Seongnam, South Korea. Electronic address: tjyoon@ajou.ac.kr.

PMID: 34781244
DOI: 10.1016/j.biomaterials.2021.121252

Abstract

It is challenging to diagnose patients with pancreatic ductal adenocarcinoma (PDAC) early on, and their treatment is often complex. Gemcitabine (GEM) is the first-line treatment for PDAC, but its efficacy is limited in most patients due to the GEM resistance from KRAS and P53 gene mutations. We describe the correction of a double gene mutation and therapeutic effect for the GEM resistant PDAC. Bio-available nanoliposomes (NL) possessing Cas9-ribonucleoproteins and adenine-base editors were developed to conduct KRAS and P53 mutation gene editing directly. NLs were conjugated with EGFR antibodies to tumor-specific delivery, and the anti-cancer effect was verified in vitro and in vivo Model. Our GEM-combinatorial therapeutic strategies using double gene editing systems with one-shot may be a potent therapy for PDAC, overcoming chemoresistance.

Keywords: Drug-resistance; Gene editing; Nanoliposome; Pancreatic cancer; Protein delivery.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma, Pancreatic Ductal* / drug therapy
Carcinoma, Pancreatic Ductal* / genetics
Cell Line, Tumor
Drug Resistance, Neoplasm / genetics
Gene Editing
Humans
Pancreatic Neoplasms* / drug therapy
Pancreatic Neoplasms* / genetics
Pharmaceutical Preparations*

Substances

Pharmaceutical Preparations