The major goal of surgical oncology is the complete resection of tumors with adequate tumor-free margins and minimal surgical morbidity, noting that surgery cures about 45% of patients, whereas chemotherapy and radiation cure only 5% of patients. In lung, breast, prostate, colon, and pancreatic cancers, a complete resection of tumors has a 3- to 5-fold increase in survival over partial or incomplete surgical resection. However, the intraoperative assessment of tumor margins is merely based on palpation and visual inspection, resulting frequently in incomplete tumor resection (R1 resections). The goal is to develop nanotechnology for """"""""see and treat"""""""" modalities in surgical oncology, enabled by polymeric micelles that emit tissue penetrating near-infrared light for delineation of tumor margins and surgical guidance;generate singlet oxygen upon intra- operative photodynamic therapy (PDT);and enhance cancer cell apoptosis by the co-delivery of gossypol, a natural BH3 mimetic that inhibits anti-apoptotic Bcl-2 proteins: Bcl-2, Bcl-xL, and Mcl-1. We have proven that poly(ethylene glycol)-block-poly(e-caprolactone) (PEG-b-PCL) assembles into nanoparticles that entrain a near-infrared dye (DiR), a photosensitizer (mTHPP), and gossypol, forming micelles that are 100 nm in diameter and slowly release all 3 components over 24 hrs. We hypothesize that PEG-b-PCL micelles filled with DiR, mTHPP, and gossypol will accumulate at solid tumors via the enhanced permeability and retention effect and """"""""light up"""""""" tumor margins, enabling surgical guidance, more complete surgical resection, and lower tumor reoccurrence. We hypothesize that laser light delivered to the """"""""lit up"""""""" region of the tumor bed (intraoperative PDT) will generate singlet oxygen that kills tumor cells, especially in concert with co-delivered gossypol.
Specific Aims : (1) To assess the stability, generation of singlet oxygen, and tumor targeting of PEG-b-PCL micelles filled with DiR, mTHPP, and gossypol by in vitro physicochemical and photophysical studies and in vivo experiments: whole body optical imaging of DiR and mTHPP and a pharmacokinetics study on gossypol. (2). To assess tumor reoccurrence after surgical guidance by PEG-b-PCL micelles filled with DiR and surgical resection of tumors and after surgical resection of tumors alone as a positive control. (3). To assess tumor reoccurrence after surgical resection and intraoperative PDT with PEG-b-PCL micelles filled with mTHPP, with or without co-incorporated gossypol. (4). To assess tumor reoccurrence after optical imaging of DiR, surgical resection, and intraoperative PDT with mTHPP and gossypol (tri-modal therapy). Advances in integrated optical imaging and therapeutic capability of biocompatible PEG-b-PCL micelles will enable tenable nano-technology applications in surgical oncology and rapid translation into clinical trials.
The goal is to develop a unique tri-functional nanocarrier for surgical oncology that can deliver near-infrared dye, photosensitizer, and gossypol together into solid tumors for intraoperative optical imaging of solid tumors and light-activated cancer cell killing. In a mouse model of neuroblastoma, we will test whether surgical guidance, surgical resection, and intraoperative light-activated cancer cell killing will maximize tumor killing, minimize collateral damage, and prolong survival.
