Development of a Novel Tumor-Targeting and Tumor-Penetrating Nanosystem for Breast Cancer Therapy
Abstract
Overarching Challenges: Revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival; eliminate the mortality associated with metastatic breast cancer. Rationale: The antitumor efficacy of nanoparticle (NP) therapeutic agents has been proven in the clinic through the use of Food and Drug Administration (FDA)-approved drugs such as albumin-bound paclitaxel (Abraxane®, Celgene), liposomal doxorubicin (Doxil®, Janssen), liposomal vincristine (Marqibo®, Spectrum Pharmaceuticals), and others. However, while these first-generation NP drugs are safe and effective, they are rarely sufficient to result in total tumor eradication and cures. The reasons for this are several but include the lack of truly selective tumor-targeting as well as the inability to adequately penetrate tumors to access all malignant cells. The concept of "cellular zip codes" that uniquely mark tumor cells, as well as tumor-associated vasculature and other cell types located within cancers such as tumor-associated macrophages (TAMs), has been developed by the research team led by Erkki Ruoslahti, MD/PhD (Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA) and others. The technology described and to be further developed herein has been exclusively licensed by EnduRx Pharma and focuses on the development of novel, next-generation NPs that leverage the concept of cellular zip codes as a means to selectively target and penetrate tumors with cytotoxic payloads that achieve superior anticancer responses including cures. Work performed by the Ruoslahti group over more than two decades and involving multiple iterative optimization steps has culminated in the development of an anticancer nanoparticle that is guided specifically to (and throughout) tumors by a proprietary tumor-targeting/penetrating peptide known as LinTT1 (Nano Lett 17:1356-1364, 2017). The tumor-homing receptor for LinTT1 is p32/gClqR/HABP, a protein selectively expressed on the cell surface of tumor cells, tumor vasculature (blood vessels, lymphatics), and TAMs. Importantly, LinTT1 does not recognize normal cells or tissues. LinTT1-based NPs can theoretically selectively deliver any of a variety of anticancer payloads such as small molecules, therapeutic nucleic acids, protein toxins, radionuclides, etc.; these NPs could potentially therefore be applied clinically as a platform anticancer targeted delivery nanosystem. In the current proposal, the LinTT1 nanosystem (alone or together with standard-of-care chemotherapy) will be employed to deliver a cytotoxic peptide –- D(KLAKLAK)2 –- that causes tumor cell killing by inducing so-called programmed cell death through disruption of the mitochondrial membranes (mitochondria-mediated apoptosis). In preclinical studies, this LinTT1-D(KLAKLAK)2 NP has been associated with dramatic antitumor responses in triple-negative breast cancer (TNBC)-bearing mice, including many cures, with no limiting toxicities. Importantly, those TNBC tumors that are not cured by treatment with a p32-targeted nanosystem acquire high expression of alpha-v integrins, alphavbeta3 in particular (J Controlled Release 268:49-56, 2017). Of note, RGD peptides, which bind integrins, are among the most commonly used ligands for tumor targeting. These findings suggest simultaneous targeting of tumors with both p32- and alphavbeta3 integrin-homing peptides (i.e., LinTT1 and RGD peptides) might prevent resistance to either therapy alone. Objective and Aims: Aim 1 will focus on the synthesis and characterization of micellar forms of p32- and alphavbeta3 integrin-targeting/tumor-penetrating NPs separate or combined, followed in Aim 2 by in vivo efficacy studies, product development, and pilot toxicology. The overarching objective is to provide the complete scientific and technical basis to enable entry of a lead and back-up NPs into Investigational New Drug (IND)-enabling studies and clinical trials. Poten
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010122
Entities
People
- Stephan Morris
Organizations
- United States Army