Abstract 1770: Viral-based nanoparticles: a new therapeutic approach for anticancer therapy
Authors: Kines Rhonda , Bhattacharya Debaditya , MacDougall John R. , Milenic Diane , Brechbiel Martin W. , Pinos Elisabet de los , Schiller John T. 
Published: May 2015

Abstract
One of the hurdles to effective cancer treatment is tumor specific targeting of drugs. We have observed, both in vitro and in vivo, that Human papillomavirus-derived nanoparticles (HPV-NPs) have an innate tropism for tumors. HPV's primary attachment factors in infection are heparan-sulfated proteoglycans (HSPG) and as tumors often upregulate HSPGs at the extracellular matrix, this may be a contributing factor for HPV's tumor tropic nature. Here we present data to support the use of HPV-NPs in the treatment of ovarian carcinoma and uveal melanoma with α-particle emitting radiation (227Th) and photodynamic therapy (PDT), respectively. We first explored in vivo tumor targeting using HPV-NPs delivering a plasmid expressing the luciferase gene. Luciferase signal was detected in SKOV-3 tumor bearing, but not control animals, and this signal was only present in tumor tissue as revealed by ex vivo imaging. This finding prompted us to explore the therapeutic effect of delivering 227Th. The agent AU-010 was constructed by conjugation of a chelator to the HPV-NPs. Th-227 was then used to radiolabel the conjugated HPV-NPs. Animals were injected with SKOV-3 tumor cells, and 10 days following implant, treatment was initiated with three weekly administrations of either AU-010 (100 nCi), free chelated-227Th (100 nCi), unlabeled HPV-NPs or saline. HPV-NP targeting of 227Th to tumors provided a significant survival advantage over the control arms, demonstrating the therapeutic potential of HPV-NPs. Currently, follow-up experiments are evaluating optimized chelators in additional animal models. We next explored the use of HPV-NPs in photodynamic therapy with the development of AU-011. AU-011 is an HPV-NP conjugated to ≈500 molecules of infrared dye, IR700 (LiCor), and when irradiated with 690 nm near-infrared light generates reactive oxygen species that are specifically and immediately lethal to dye bound cells. This technology was initially validated using Trastuzumab as a targeting agent (Mitsunaga et al, Nat Med 17(12):1685-91, 2011). We compared the cell binding activity of AU-011 and Trastuzumab-IR700 on SKOV-3 ovarian cancer cells in vitro and observed a higher binding capacity of AU-011. We next compared the killing activity of the two agents. Trastuzumab-IR700 was found to have an IC50 value of 1.6 nM when activated with 32 J of 690 nm light. By comparison, AU-011 was found to have an IC50 value of 5.6 pM when activated with 16 J of 690 nm light. Thus, AU-011 appeared to be considerably more potent than Trastuzumab-IR700. Finally, we extended these observations to a panel of uveal melanoma cell lines. We chose uveal melanoma because PDT with 690 nm light is FDA approved and used regularly in the ophthalmic clinic. When applied on the melanoma cell lines, AU-011 was found to show high cell binding and potent cell killing. Currently, proof-of-concept in vivo studies of AU-011 in uveal melanoma are underway, paving the way to clinical development for this indication.
Citation Format: Rhonda Kines, Debaditya Bhattacharya, John R. MacDougall, Diane Milenic, Martin W. Brechbiel, Elisabet de los Pinos, John T. Schiller. Viral-based nanoparticles: a new therapeutic approach for anticancer therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1770. doi:10.1158/1538-7445.AM2014-1770