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Biomaterials. 2017 Nov;145:207-222. doi: 10.1016/j.biomaterials.2017.08.035. Epub 2017 Aug 23.

Synergistic antitumor effect mediated by a paclitaxel-conjugated polymeric micelle-coated oncolytic adenovirus.

Author information

1
Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Republic of Korea.
2
Center for Controlled Chemical Delivery, Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, 84112, USA.
3
Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, 63130, USA.
4
Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Republic of Korea; Center for Controlled Chemical Delivery, Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, 84112, USA.
5
Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Republic of Korea. Electronic address: chaeok@hanyang.ac.kr.

Abstract

Combination treatment consisting of oncolytic adenovirus (Ad) and paclitaxel (PTX) is a promising strategy to achieve synergistic antitumor effect. However, a co-administration approach is subject to inherent limitations due to the poor solubility of PTX and chemoresistance of tumor cells. In order to overcome these limitations, an oncolytic Ad expressing a p53 variant (oAd-vp53) that is resistant to p53 inactivation in the tumor microenvironment was complexed with PEGylated and PTX-conjugated polymeric micelle (APP). This approach generated an oAd-vp53/APP complex (176.4 nm in diameter) that could concurrently deliver both oncolytic Ad and the nanoparticulate drug APP to tumors. APP-complexed replication-incompetent Ad (dAd/APP) exhibited 12-fold higher transduction efficiency than naked dAd in coxsackie adenovirus receptor (CAR)-negative cancer cells. This increased efficiency was attributed to more efficient cellular internalization mediated by charge interactions between APP and anionic cell membranes. Furthermore, oAd-vp53/APP elicited synergistically higher cancer cell killing than naked oAd-vp53, APP, or oAd-vp53 in combination with PTX (oAd-vp53 + PTX); this synergistic effect was shown to be due to superior induction of apoptosis and viral replication. Importantly, oAd-vp53/APP induced more potent and synergistic antitumor effect through both local and systemic administration by enhancing replication of oncolytic Ad and induction of apoptosis in tumor tissue. Further, the APP coating on the surface of Ad markedly attenuated the host immune response against Ad and decreased hepatic sequestration, resulting in minimal hepatotoxicity and a good safety profile. These attributes enabled oAd-vp53/APP to elicit potent antitumor effect over multiple treatment cycles. Altogether, we demonstrate that concurrent delivery of oncolytic Ad and APP as a single nanocomplex is a promising strategy for achieving synergistic antitumor effect.

KEYWORDS:

Breast cancer; Cationic polymer; Gene therapy; Oncolytic adenovirus; Paclitaxel

[Indexed for MEDLINE]

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