Abstract
Oncolytic virotherapy has the disadvantage of being unsuitable for systemic delivery due to immune elimination. Liposomal encapsulation is well-recognized to reduce immune elimination and enhance the stability of drugs in the bloodstream. In the present study, the potential of liposome-encapsulated plasmid DNA of telomerase-specific oncolytic adenovirus (TelomeScan) expressing GFP (Lipo-pTS) as an oncolytic adenoviral agent suitable for systemic delivery was investigated. Lipo-pTS, which has a diameter of 40–50 nm, showed potent antitumor effects on HCT116 colon carcinoma cells in vitro and in vivo. Tumor selectivity of Lipo-pTS was independent of coxsackie and adenovirus receptor (CAR). Importantly, Lipo-pTS reduced production of adenovirus-neutralizing antibodies (AdNAbs) after intravenous administration into immune-competent mice compared to TelomeScan, and even in the presence of AdNAbs, Lipo-pTS maintained strong cytotoxicity. In conclusion, Lipo-pTS has the potential to become an oncolytic adenoviral agent suitable for systemic delivery with the characteristics of CAR-independent antitumor activity and a stealth effect on the immune system.
Highlights
Oncolytic virotherapy is an emerging strategy for cancer treatment
Oncolytic viruses have been developed worldwide since the 1990s based on the traits of strong cytotoxicity that viruses originally possess and ideal tumor specificity, which comes from appropriate genetic modification, and the first oncolytic viral agent, named talimogene laherparepvec (T-VEC), was approved by the US Food and Drug Administration (FDA) in 2015 for the treatment of melanoma based on a successful phase III clinical trial in which T-VEC intratumoral injection decreased in size by ≥50 % 64% of injected lesions, and 34% of uninjected non-visceral lesions and even 15% of visceral lesions, which means that local injection of oncolytic viruses interestingly induced systemic immunotherapeutic effects against melanoma, in addition to direct cytotoxic effects on the local lesions[16]
As for the use of nanoparticles in gene delivery, many types of nanoparticles have been developed as carriers of nucleic acids such as DNA, mRNA, siRNA, and miRNA, and some of the lipid-based and polymer-based nanoparticle-mediated gene therapies are currently being tested in clinical trials, though none of them has yet become commercially available[21,22]
Summary
Oncolytic virotherapy is an emerging strategy for cancer treatment. Many oncolytic viruses have been developed from various types of viruses, such as adenovirus, herpes simplex virus, vaccinia virus, reovirus, poxvirus, and picornavirus, and some of them have been tested in clinical trials[1,2,3]. One is that encapsulated adenoviruses by liposome are likely to become too big (larger than 100 nm) to take advantage of the EPR effect, judged by the fact that an adenovirus itself has a diameter of 80 to 100 nm. Another is the issue of the nature of adenovirus infectivity; the original adenoviruses are internalized into cells through a multistep process that starts with attachment of the adenovirus capsids including the fiber proteins to the coxsackie and adenovirus receptor (CAR) on the cell surface. The potential of this liposome-encapsulated adenoviral plasmid DNA as a systemically-deliverable oncolytic adenovirus in vitro and in vivo was evaluated by examining the antitumor effect, CAR independency in virus infection, and the effect of the immune system, especially via neutralizing antibodies to adenovirus
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