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Thai Minh Duy LeThai Minh Duy Le

한양대학교

ACS Nano, Oct 02 2024, | https://doi.org/10.1021/acsnano.4c02165 Smart Accumulating Dual-Targeting Lipid Envelopes Equipping Oncolytic Adenovirus for Enhancing Cancer Gene Therapeutic Efficacy

Yuebin Zhao^1†, Thai Minh Duy Le^1†, Jinwoo Hong⁴, Ao Jiao¹, A-Rum Yoon^1,2,3, Chae-Ok Yun^1,2,3,4*

1Department of Bioengineering, College of Engineering, Hanayang University, Seoul 04763, South Korea

2Institute of Nano Science and Technology (INST), Hanayang University, Seoul 04763, South Korea

3Hanyang Institute of Bioscience and Biotechnology (HY-IBB), Hanyang University, Seoul 04763, South Korea

4GeneMedicine CO., Ltd., Seoul 04763, South Korea

^†These authors contributed equally to this work.

^*Correspondence should be addressed to Chae-Ok Yun

Abstract

Systemic delivery of oncolytic adenovirus (oAd) for cancer gene therapy must overcome several limitations such as rapid clearance from the blood, nonspecific accumulation in the liver, and insufficient delivery to the tumor tissues. In the present report, a tumor microenvironment-triggered artificial lipid envelope composed of a pH-responsive sulfamethazine-based polymer (PUSSM)-conjugated phospholipid (DOPE-HZ-PUSSM) and another lipid decorated with epidermal growth factor receptor (EGFR) targeting peptide (GE11) (GE11-DOPE) was utilized to encapsulate replication-incompetent Ad (dAd) or oAd coexpressing short-hairpin RNA (shRNA) against Wnt5 (shWnt5) and decorin (dAd/LP-GE-PS or oAd/LP-GE-PS, respectively). In vitro studies demonstrated that dAd/LP-GE-PS transduced breast cancer cells in a pH-responsive and EGFR-specific manner, showing a higher level of transduction than naked Ad under a mildly acidic pH of 6.0 in EGFR-positive cell lines. In vivo biodistribution analyses revealed that systemic administration of oAd/LP-GE-PS leads to a significantly higher level of intratumoral virion accumulation compared to naked oAd, oAd encapsulated in a liposome without PUSSM or EGFR targeting peptide moiety (oAd/LP), or oAd encapsulated in a liposome with EGFR targeting peptide alone (oAd/LP-GE) in an EGFR overexpressing MDA-MB-468 breast tumor xenograft model, showing that both pH sensitivity and EGFR targeting ability were integral to effective systemic delivery of oAd. Further, systemic administration of all liposomal oAd formulations (oAd/LP, oAd/LP-GE, and oAd/LP-GE-PS) showed significantly attenuated hepatic accumulation of the virus compared to naked oAd. Collectively, our findings demonstrated that pH-sensitive and EGFR-targeted liposomal systemic delivery of oAd can be a promising strategy to address the conventional limitations of oAd to effectively treat EGFR-positive cancer in a safe manner.

논문정보

형식Research article
게재일2024년 10월 (BRIC 등록일 2024-10-14)
연구진국내 연구진
분야 생명과학 > 유전자발현

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