This is a competitive renewal proposal of the R01 CA115483 grant after 9 years. In our last competitive renewal 4 years ago, we proposed to develop a novel oligocholic acid/PEG based nanoplatform to load paclitaxel (PTX) and SN-38 for targeted delivery via i.v. and i.p. for OvCa therapy. We also proposed to use [14C]-labeled paclitaxel to determine the in vivo biodistribution and OvCa targeting properties of PTX-loaded nanocarriers, in both subcutaneous and intraperitoneal OvCa xenograft models. This last 4 year grant support resulted in 24 publications and 3 patent applications. In this second competitive renewal, we propose to further develop our oligocholic acid/PEG based nanoplatform by (i) incorporating novel strategies for efficient display of targeting ligands, and (ii) chemical tuningof the cholic acid core of the amphiphilic telodendrimer (monomer unit) for high capacity loading of a wide range of anti-cancer drugs. These novel concepts will be systematically applied to the basic nanoplatform one at a time and the resulting nanoparticles will be fully characterized for their physicochemical properties and their in vivo tumor targeting properties. Those superior features will then be combined and adopted to the development of a novel third generation targeting nanocarrier that is highly versatile, multifunctional, easy to formulate in the clinics, nd can function as an efficacious drug delivery system for cancer therapy. We will continue to use OvCa xenograft, subcutaneous and intraperitoneal models, to evaluate these novel nanoconstructs. We have previously demonstrated that therapeutic efficacy of telodendrimer-based micellar nanoparticles developed in our laboratory can be enhanced by (i) introducing inter- telodendrimer covalent but reversible crosslinkages to improve the in vivo stability of the nanocarrier, and (ii) by decorating the surface of the nanocarrier with tumor targeting ligands such as OA02 (a cyclic peptide) against ?3?1 integrin. The next generation telodendrimer- based micellar nanoparticle will (i) enable improvement of targeting ligand display, and (ii) increase the range of therapeutic pay-loads suitable for the nanoplatform. We believe these improvements will greatly enhance the versatility and in vivo efficacy of these nanoparticle drugs, not only in xenograft or transgenic murine tumor models, but also in clinical OvCa. In this Competitive Renewal Proposal, we plan to pursue the following specific aims: 1. To improve the ligand display on our micellar nanocarrier 2. To develop new hybrid telodendrimers that can nanoformulate drugs that otherwise cannot be nanoformulated with our existing telodendrimers. 3. Promising nanocarriers from aim 1 and 2 will be selected and evaluated in subcutaneous and intraperitoneal OvCa xenograft models in nude mice for biodistribution and therapeutic efficacies.

Public Health Relevance

This is a competitive renewal proposal of the R01 CA115483 grant after 9 years. We have previously demonstrated that therapeutic efficacy of telodendrimer-based micellar nanoparticles developed in our laboratory can be enhanced by (i) introducing inter-telodendrimer covalent but reversible crosslinkages to improve the in vivo stability of the nanocarrier, and (ii) by decorating the surface of the nanocarrier with tumor targeting ligands such as OA02 (a cyclic peptide) against ?3?1 integrin. The next generation telodendrimer-based micellar nanoparticle will (i) enable improvement of targeting ligand display, and (ii) increase the range of therapeutic pay- loads suitable for the nanoplatform. We believe these improvements will greatly enhance the versatility and in vivo efficacy of these nanoparticle drugs, not only in xenograft or transgenic murine tumor models, but also in clinical OvCa.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA115483-14
Application #
9477423
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Fu, Yali
Project Start
2015-05-01
Project End
2020-04-30
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
14
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California Davis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Luo, Yan; Wu, Hao; Feng, Caihong et al. (2017) ""One-Pot"" Fabrication of Highly Versatile and Biocompatible Poly(vinyl alcohol)-porphyrin-based Nanotheranostics. Theranostics 7:3901-3914
Carney, Randy P; Hazari, Sidhartha; Colquhoun, Macalistair et al. (2017) Multispectral Optical Tweezers for Biochemical Fingerprinting of CD9-Positive Exosome Subpopulations. Anal Chem 89:5357-5363
Xiao, Kai; Lin, Tzu-Yin; Lam, Kit S et al. (2017) A facile strategy for fine-tuning the stability and drug release of stimuli-responsive cross-linked micellar nanoparticles towards precision drug delivery. Nanoscale 9:7765-7770
Xiao, Wenwu; Suby, Nell; Xiao, Kai et al. (2017) Extremely long tumor retention, multi-responsive boronate crosslinked micelles with superior therapeutic efficacy for ovarian cancer. J Control Release 264:169-179
Carney, Randy P; Thillier, Yann; Kiss, Zsofia et al. (2017) Combinatorial Library Screening with Liposomes for Discovery of Membrane Active Peptides. ACS Comb Sci 19:299-307
Liu, Ruiwu; Li, Xiaocen; Lam, Kit S (2017) Combinatorial chemistry in drug discovery. Curr Opin Chem Biol 38:117-126
Yang, Xixiao; Xue, Xiangdong; Luo, Yan et al. (2017) Sub-100nm, long tumor retention SN-38-loaded photonic micelles for tri-modal cancer therapy. J Control Release 261:297-306
He, Wei; Felderman, Martina; Evans, Angela C et al. (2017) Cell-free production of a functional oligomeric form of a Chlamydia major outer-membrane protein (MOMP) for vaccine development. J Biol Chem 292:15121-15132
Bharadwaj, Gaurav; Nhan, Viet; Yang, ShanChao et al. (2017) Cholic acid-based novel micellar nanoplatform for delivering FDA-approved taxanes. Nanomedicine (Lond) 12:1153-1164
Lin, Tzu-Yin; Guo, Wenchang; Long, Qilai et al. (2016) HSP90 Inhibitor Encapsulated Photo-Theranostic Nanoparticles for Synergistic Combination Cancer Therapy. Theranostics 6:1324-35

Showing the most recent 10 out of 43 publications