Journal
ACS NANO
Volume 12, Issue 10, Pages 9894-9902Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsnano.8b02813
Keywords
virotherapy; tumor microenvironment; nanoparticle; lactate oxidase; photodynamic therapy
Categories
Funding
- Taiwan Ministry of Science and Technology [MOST105-2628-E-110-001-MY3, MOST105-2628-B-110-004-MY3, MOST105-2218-E-002-031, MOST106-2314-B-002-051-MY3, MOST106-2314-B-002-103-MY2, 107-0210-01-19-01]
- Academia Sinica Research Program on Nanoscience and Nanotechnology [2399-105-0200]
- Foundation for the Advancement of Outstanding Scholarship
- Academia Sinica
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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.
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