We hypothesize that selective targeting of integrin ?v?3 by a small-molecule antagonist and an RGD-paclitaxel conjugate will have safety and efficacy profiles suitable for clinical studies. The purposes of this study are to (A) develop AV38, our highly selective integrin ?v?3 receptor antagonist as a novel anti-neoplastic agent for non-small cell lung cancer (NSCLC) alone and in combination with paclitaxel;(B) conjugate AV38 to paclitaxel and use this conjugate as well as our recently described RGD-paclitaxel as a selective delivery mechanism to ?v?3 receptor-positive cancer cells;and (C) monitor these processes by multimodality imaging techniques such as positron emission tomography (PET), bioluminescence imaging (BLI), and microCT. The rationale behind this proposal comes from the following observations: (A) integrin ?v?3 is overexpressed in cancer cells and in the malignant neovascular endothelium;(B) lung cancer cells are highly metastatic and the adhesion, invasion of cells into the matrix of metastatic organs, and subsequent tumoral angiogenesis is mediated, in part, by ?v?3;(C) combination of targeted therapy with conventional chemotherapy increase the efficacy of therapy without additional toxicity;and (D) several antagonists of ?v?3 are entering into clinical and preclinical studies in a variety of disease models but their potential in NSCLC has yet to be studied. To test our overarching hypothesis more specifically we propose:
Specific Aim 1 : To develop an RGD-paclitaxel conjugate with optimal receptor affinity and cytotoxicity. We hypothesize that integrin targeted delivery of paclitaxel allows preferential cytotoxicity to lung cancer cells depending on integrin expression levels.
Specific Aim 2 : To develop AV38, a novel small-molecule integrin antagonist as a single agent, in combination with paclitaxel, and as a paclitaxel-conjugate. We hypothesize that non-peptide integrin antagonists are efficient for integrin specific delivery of paclitaxel due to their relatively high metabolic stability and ease of synthesis.
Specific Aim 3 : To evaluate the integrin-targeted delivery efficacy and in vivo pharmacokinetics of the paclitaxel conjugates developed in Aims 1 and 2. We hypothesize that in vivo pharmacokinetics and pharmacodynamics of paclitaxel conjugates are highly correlated with in vitro receptor affinity and cytotoxicity as well as other characters such as molecular size, hydrophilicity, metabolic stability, and molecular charge.
Specific Aim 4 : To evaluate the anti-tumor effect of the paclitaxel conjugates by means of tumor size monitoring, histopathology and non- invasive molecular imaging. We will test the hypothesis that tumor delivery of the paclitaxel conjugate is most effective to integrin positive lung cancer. We have developed a novel drug conjugate system to deliver maximum dose to both tumor cells and tumor vasculature with dual anti-tumor effects. This new treatment regimen has its greatest potential in patients with tumors that overexpress integrin ?v?3. These tumors are usually highly metastatic as in non-small cell lung cancer (NSCLC). Because most solid tumors are angiogenesis dependent and express integrin on their cell surface, drugs developed in this project are also applicable to many other tumor types such as brain, breast, ovarian, prostate, and colon cancer.
|Wang, Zhe; Huang, Peng; Bhirde, Ashwinkumar et al. (2012) A nanoscale graphene oxide-peptide biosensor for real-time specific biomarker detection on the cell surface. Chem Commun (Camb) 48:9768-70|