Targeting Tumor Microenvironment by Bioreduction-Activated Nanoparticles for Light-Triggered Virotherapy
Journal
ACS Nano
Date Issued
2018
Author(s)
Abstract
Solid tumors characteristically display higher levels of lactate production due to anaerobic metabolism of glucose. Meanwhile, the U.S. Food and Drug Administration (FDA) has approved virotherapy for use in cancer treatment; however systemic administration remains as a particular challenge. Here we report exploitation of tumor lactate production in designing a hypoxia-responsive carrier, self-assembled from hyaluronic acid (HA) conjugated with 6-(2-nitroimidazole)hexylamine, for localized release of recombinant adeno-associated virus serotype 2 (AAV2). The carrier is loaded with lactate oxidase (LOX) and is permeable to small molecules such as the lactate that accumulates in the tumor. Subsequently, LOX oxidizes the lactate to pyruvate inside the carrier, accompanied by internal lowering of oxygen partial pressure. Bioreduction of the 2-nitroimidazole of the HA conjugated with 6-(2-nitroimidazole)hexylamine converts it into a hydrophilic moiety and electrostatically dissociates the carrier and virus. Efficacious and specific delivery was proven by transduction of a photosensitive protein (KillerRed), enabling significant limitation in tumor growth in vivo with photodynamic therapy. An approximate 2.44-fold reduction in tumor weight was achieved after a 2-week course, compared with control groups. Furthermore, conjugation of the AAV2 with iron oxide nanoparticles ("magnetized" AAV2) facilitated magnetic resonance imaging tracking of the virus in vivo. Taken together, the solid tumor microenvironment promotes bioreduction of the lactate-responsive carrier, providing rapid and specific delivery of AAV2 for light-triggered virotherapy via systemic administration. ? 2018 American Chemical Society.
SDGs
Other Subjects
Controlled drug delivery; Hyaluronic acid; Iron oxides; Magnetic resonance imaging; Nanomagnetics; Nanoparticles; Photodynamic therapy; Tumors; Viruses; Food and Drug Administration; Iron oxide nanoparticle; Lactate oxidase; Oxygen partial pressure; Recombinant adeno-associated virus; Systemic administration; Tumor microenvironment; Virotherapy; Targeted drug delivery; antineoplastic agent; lactate 2-monooxygenase; lactic acid; mixed function oxidase; nanoparticle; photosensitizing agent; animal; Bagg albino mouse; biosynthesis; cell culture; cell proliferation; chemistry; drug effect; HEK293 cell line; human; isolation and purification; lung tumor; metabolism; mouse; nuclear magnetic resonance imaging; nude mouse; Parvovirinae; pathology; photochemotherapy; tumor microenvironment; Animals; Antineoplastic Agents; Cell Proliferation; Cells, Cultured; HEK293 Cells; Humans; Lactic Acid; Lung Neoplasms; Magnetic Resonance Imaging; Mice; Mice, Inbred BALB C; Mice, Nude; Mixed Function Oxygenases; Nanoparticles; Parvovirinae; Photochemotherapy; Photosensitizing Agents; Tumor Microenvironment
Publisher
American Chemical Society
Type
journal article