This project is developing tumor-targeted delivery of multifunctional nanoparticles packaged with therapeutic agents in order to maximize the antitumor effect and lower toxicity to the prostate cancer patient. The Wang lab from the Viterbi School of Engineering will team up with the Wong lab from the Keck School of Medicine to test a hypothesis that crosslinked multilamellar lipsomes (CMLs) displaying a tumor vasculature-specific peptide RRL can achieve targeted delivery of the anticancer reagent doxorubicin (Dox) to prostate tumors, and that such a form of nanomedicine can improve our ability to treat cancer. Three specific aims are devised to test this hypothesis.
• Synthesize and characterize the RRL-lipDox nanoparticle. In this aim, we plan to use a 4-step protocol to synthesize the nanoparticle RRL-lipDox, which is a Dox- encapsulating crosslinked multilamellar liposome with the surface-displayed tumor vasculature- specific peptide RRL. Parameters such as size, stability, encapsulation efficiency, in vitro release kinetics and cytotoxicity of the synthesized particle will be extensively characterized.
• Assess the selective binding of RRL-lipDox to tumor tissues in vitro. Prostate tumor-associated cell lines and human prostate cancer cryosections will be used to test the capability of RRL-lipDox to selectively bind to tumor tissues. Assays will also be conducted to determine the spatial relationship between nanoparticles and prostate tumor microenvironment.
• Examine the pharmacokinetics and in vivo potency of RRL-lipDox in preclinical mouse models. Pharmacokinetics, biodistribution, and toxicity of RRL-lipDox will be determined in mice. The human prostate xenograft model and the murine prostate transplantation model will be used to assess the ability of RRL-lipDox to target tumors and mount antitumor responses.
Innovation and Significance
The crosslinked multilamellar lipsome is a newly designed nanoparticle. RRL is an entirely new peptide capable of targeting tumor vasculature. From a scientific perspective, our proposed nanoparticle can become versatile platform technology for targeted delivery of various therapeutic reagents to different tumors. The success of this project has the potential to foster a paradigm shift in treating prostate and other malignant tumors. Successful implementation of our strategy will cure more individuals suffering from advanced cancer since it will now become possible to dose-escalate and dose- intensify cancer therapy resulting in a higher response rate against the targeted tumor with minimal toxicity to the patient. Targeted delivery will also allow for direct manipulation of the tumor and its microenvironment and open the possibility of synergistic combination therapies such as radiation, chemo-, immuno-, and cytotoxic therapy, thus vastly expanding the therapeutic repertoire.
