UC San Diego
Development of Liposomal and Silica Nanoparticles for Oncolytic Viral Gene Therapy and Cancer Immunotherapy
- Author(s): Mendez, Natalie
- Advisor(s): Kummel, Andrew C
- et al.
Nanoparticle technologies have been emerging as drug-loaded carriers since they may be engineered to actively or passively target cancer cells, reduce toxicity and side effects, improve drug stability and pharamacokinetics, and enhance drug potency. Although substantial progress has been made over the years, some limitations include rapid clearance, altered drug potency, and non-specific uptake by healthy tissues. Studies have shown that size, shape, material and composition of a nanoparticle can dramatically alter its efficacy, toxicity, and biodistribution, among other functions. To address this, two different drug delivery systems, liposomal and silica-based nanoparticles, have been designed as drug delivery vehicles for oncolytic viral gene therapy and cancer immunotherapy, respectively.
Oncolytic viruses (OVs) constitute a promising class of cancer therapeutics which exploit validated genetic pathways known to be deregulated in many cancers. To overcome antibody neutralization and to enhance its efficacy, a method for liposomal encapsulation of adenovirus was developed. The encapsulation of adenovirus in non-toxic anionic lecithin-cholesterol-PEG liposomes ranging from 140 to 180 nm in diameter were prepared by self-assembly around the viral capsid. Furthermore, an immunoprecipitation (IP) technique was developed as a fast and effective method to extract non-encapsulated viruses and homogenize the liposomes remaining in solution. 78% of adenovirus plaque forming units were encapsulated and retained infectivity after IP processing. Additionally, encapsulated viruses showed to enhance transfection efficiency compared to non-encapsulated Ads.
In addition, a silica-based nanoparticle system was developed to enhance the efficacy of a Toll-like receptor 7 agonist (TLR7). TLR7 agonists have gained great interest in cancer research due to their antitumoral activity and are being investigated as potent adjuvants to treat cancer. A TLR7 agonist, 1V209, was conjugated to 100nm silica nanoparticles and its properties were assessed using various analytical methods and in vitro and in vivo assays. These studies showed that the immunostimulatory properties of 1V209 were enhanced when conjugated to 100nm silica nanoshells both in vitro and in vivo. Both liposomal and silica-based nanoparticle platforms showed to enhance the properties of oncolytic viruses and cancer immune adjuvants, respectively.