Abstract LB-3: Fully synthetic self-assembling tumor-targeted virus-like nanoparticles .

Abstract

Abstract Virus particles have evolved as highly effective delivery systems. They are able to deliver whole proteins and large nucleic acid molecules to certain types of cells. Genetically engineered virus-like particles (VLPs) have been explored as drug delivery and imaging agents. However, generation of fully synthetic VLPs has not been achieved. We have found that properly derivatized synthetic analogs of transmembrane domains not only inhibit the function of the corresponding receptor, but can self-assemble into virus-like particles with high precision (Proc. Natl. Acad. Sci. U. S. A 108: 9798 (2011). The described particles have intrinsic biological activity of the peptide they are composed of and fuse with cell spontaneously. Particles composed of CXCR4 antagonist fuse spontaneously with cell membrane, inhibit CXCR4 function in vitro and CXCR4-mediated metastasis in vivo. However, the fusion is non-selective. We have now developed the first fully synthetic VLPs that fuse with cells like real viruses, in receptor-mediated manner. Prevention of non-selective fusion was achieved by derivatization of self-assembling peptides with polyethylene glycol. Addition of ligands recognizing receptors over expressed on prostate tumor cells allowed for the particles that fuse selectively with receptor-positive cells. Particles targeting gastrin-releasing peptide receptor (GRPR), luteinizing hormone-releasing hormone (LHRH) receptor and prostate-specific membrane antigen (PSMA) are remarkably stable, more than 99 % homogeneous in size and undergo receptor-mediated fusion with tumor cells expressing corresponding receptor. Whole- animal fluorescence tomography of nude mice injected with fluorescent nanoparticles targeted to PSMA and GRPR revealed that particles rapidly accumulate in tumors and allow for tumor detection as early as two hours after the injection. Development of fully synthetic VLPs establishes a foundation for generation of delivery systems with investigator-defined biophysical properties and targeting ability for a wide range of biomedical applications. Tumor-targeted self-assembling particles represent a new class of agents with dual and triple biological activity for the therapy and detection of tumors. Citation Format: Nadya Tarasova, Yuhong Chen, Marzena Dyba, Sergey G. Tarasov. Fully synthetic self-assembling tumor-targeted virus-like nanoparticles . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-3. doi:10.1158/1538-7445.AM2013-LB-3