Anticancer therapies are often compromised by nonspecific effects and challenged by tumour environments’ inherent physicochemical and biological characteristics. Often, therapeutic effect can be increased by addressing multiple parameters simultaneously. Here we report on exploiting extravasation due to inherent vascular leakiness for the delivery of a pH-sensitive polymer carrier. Tumours’ acidic microenvironment instigates a charge reversal that promotes cellular internalization where endosomes destabilize and gene delivery is achieved. We assess our carrier with an aggressive non-small cell lung carcinoma (NSCLC) in vivo model and achieve >30% transfection efficiency via systemic delivery. Rejuvenation of the p53 apoptotic pathway as well as expression of KillerRed protein for sensitization in photodynamic therapy (PDT) is accomplished. A single administration greatly suppresses tumour growth and extends median animal survival from 28 days in control subjects to 68 days. The carrier has capacity for multiple payloads for greater therapeutic response where inter-individual variability can compromise efficacy.
Clinical virotherapy has been successfully approved for use in cancer treatment by the U.S. Food and Drug Administration; however, a number of improvements are still sought to more broadly develop virotherapy. A particular challenge is to administer viral therapy systemically and overcome limitations in intratumoral injection, especially for complex tumors within sensitive organs. To achieve this, however, a technique is required that delivers the virus to the tumor before the body's natural self-defense eradicates the virus prematurely. Here we show that recombinant adeno-associated virus serotype 2 (AAV2) chemically conjugated with iron oxide nanoparticles (∼5 nm) has a remarkable ability to be remotely guided under a magnetic field. Transduction is achieved with microscale precision. Furthermore, a gene for production of the photosensitive protein KillerRed was introduced into the AAV2 genome to enable photodynamic therapy (PDT), or light-triggered virotherapy. In vivo experiments revealed that magnetic guidance of "ironized" AAV2-KillerRed injected by tail vein in conjunction with PDT significantly decreases the tumor growth via apoptosis. This proof-of-principle demonstrates guided and highly localized microscale, light-triggered virotherapy.
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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