Polymeric micelles for multi-drug delivery and optical imaging in surgical oncology.

摘要

To date, surgery is the most effective cancer treatment. However, traditional surgery under visual observation and by palpation limits detection of small metastatic tumor nodules. Optical near-infrared (NIR) fluorescence imaging has the clinical potential to improve cancer surgery by providing real-time guidance in the operation room. This technology would allow surgeons to conduct traditional white-light surgery with the intention of maximal macroscopic tumor resection and then reinvestigate suspicious regions and microscopic tumor nodules using intraoperative NIR fluorescence imaging.;Polymeric micelles are a promising class of nanocarriers for delivering NIR fluorescence imaging agents to tumors and providing real-time surgical guidance by the enhanced permeability and retention (EPR), tumor priming, and active targeting effects.;Poly(ethylene glycol)-block-poly(epsilon-caprolactone) (PEG-b-PCL) micelles carrying 1,1'- dioctadecyltetramethyl indotricarbocyanine iodide (DiR) passively targeted (by the EPR effect) and delineated LS180 solid colon tumors with a high tumor-to-muscle ratio in fluorescent images.;Solid tumor visualization in LS180 colon cancer-bearing animals was enhanced by the tumor priming effect, which was achieved by a 2-step strategy. (1) A single IV injection of poly(ethylene glycol)-block-poly(D,L-lactic acid) (PEG-b-PLA) micelles carrying paclitaxel, 17-allylamino-17-demethoxygeldanamycin, and rapamycin debulked LS180 solid tumors and induced apoptosis exclusively in tumors (2) Penetration of IV administered PEG-b-PCL micelles carrying DiR into the primed LS180 solid tumors was facilitated and resulted in a heightened NIR optical signal for the enhanced tumor delineation.;Lastly, actively targeted apoptosis NIR imaging was obtained by a 2-step strategy in an ES-2-luc metastatic intraperitoneal (IP) ovarian cancer model: (1) A single IP injection of PEG-b-PCL micelles carrying paclitaxel, cyclopamine, and gossypol debulked IP metastatic tumors and induced significant apoptosis in tumors. (2) IV injected apoptosis-targeting GFNFRLKAGAKIRFGS-PEG- b-PCL micelles carrying DiR actively targeted apoptotic tumors, visualized highly metastatic tumors with improved tumor specificity, and provided intraoperative optical imaging for surgical guidance. Intraoperative optical imaging surprisingly permitted identification of tumor nodules as small as 1 mm, enabled more detailed surgical performance, increased surgical accuracy, and decreased residual tumor tissues left undissected in animals.;These results suggest that the polymeric micelle system may be seamlessly integrated into surgical oncology, enhancing visualization of tumors and providing valuable guidance using intraoperative NIR fluorescence imaging.