"Double-punch" strategy for delivery of viral immunotherapy with prolonged tumor retention and enhanced transfection efficacy. J Control Release 2021 Jan 10;329:328-336
Date
12/06/2020Pubmed ID
33278479Pubmed Central ID
PMC7904666DOI
10.1016/j.jconrel.2020.11.043Scopus ID
2-s2.0-85097716937 (requires institutional sign-in at Scopus site) 12 CitationsAbstract
Viral immunotherapy has shown clinical efficacy in treating cancers (e.g., melanoma). Given that viral immunotherapy commonly uses intratumoral injection, prolonging the duration of therapeutic virus at the tumor site can further enhance the antitumor efficacy and reduce potential off-target effects. In this work, we describe a "double-punch" strategy by combining dendrimer platform and injectable hydrogel encapsulation for delivery of an adenovirus encoding Flagrp170 (Adv-Flagrp170), which has been shown to effectively mount a cytotoxic T lymphocyte response through enhanced tumor immunogenicity and optimized antigen cross-presentation. We first complexed PAMAM generation 4 (G4) with Adv (G4/Adv) to strengthen its transfection efficiency and then loaded G4/Adv into a biocompatible and injectable supramolecular hydrogel (SH) made of α-cyclodextrin and 4-arm polyethylene glycol via host-guest interaction. When tested in a murine melanoma model, the G4/Adv complex was shown to have improved retention at the tumor site. The presence of SH facilitated the targeted gene expression in tumor-infiltrating leukocytes, including antigen-presenting dendritic cells. Delivery of Adv-Flagrp170 by both G4 coating and SH encapsulation significantly enhanced its therapeutic efficacy in controlling mouse melanoma (8-fold reduction in tumor volume), which is associated with increased immune activation in the tumor microenvironment as well as decreased adenovirus-reactive antibodies. Taken together, this new formulation may be used to improve the treatment outcome of adenovirus-based cancer immunotherapy.
Author List
Wang J, Guo C, Wang XY, Yang HAuthor
Hu Yang PhD Chair, Professor in the Biomedical Engineering department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdenoviridaeAnimals
Antigens, Neoplasm
Immunotherapy
Mice
T-Lymphocytes, Cytotoxic
Transfection
