Minibeam Radiation Therapy Enhanced Delivery of Nanoparticle Anticancer Agents to Pancreatic Cancer Tumors

点击翻译按钮获取中文摘要

PROJECT SUMMARY / ABSTRACT: Nanoparticles (NPs) hold great promise for delivering more effective and safer cancer treatment than the small molecule drugs that are commonly used. This is based on studies reporting that these agents can potentially achieve greater exposure in solid tumors. However, these promises are largely hampered by a low and inefficient tumor uptake in which only 5-10% of NPs in the plasma are actually distributed from plasma to solid tumors. Certain tumors, such as pancreatic cancer (PaCa), have even greater inherent barriers to the tumor delivery of NPs. Thus, there is a strong need to discover methods that can significantly and safely enhance the overall delivery of NPs to tumors. Our overall hypothesis is that induction minibeam radiation therapy (MRT), a novel radiation treatment, is such a method. Whereas, conventional broad beam radiation (BRT) only moderately enhances drug delivery to tumors (0.2- to 2-fold). MRT is an experimental radiation therapy with unique spatial and dosimetric characteristics that are drastically different from conventional BRT. Solid preclinical studies have demonstrated that MRT is capable of an ultra-high therapeutic ratio. We recently discovered that MRT, in contrast to BRT, modifies tumor vasculature and increases tumor perfusion. We hypothesize that we can take advantage of the changes in tumor perfusion induced by MRT to significantly and safely enhance NP delivery to tumors compared to NPs alone or after BRT. This hypothesis is supported by our extensive results in genetically engineered mouse models (GEMMs) of breast cancer where induction MRT prior to administration of PEGylated liposomal doxorubicin (Doxil®; PLD) enhanced the delivery of PLD to tumors by an unprecedented magnitude of 6- to 10-fold and the enhancement was sustained safely with weekly treatments. In addition, MRT produced a 4-fold greater increase in the tumor delivery of PLD to GEMMs of breast cancer, which was associated with higher levels of overall and PD-L1 expressing macrophages compared to BRT. Our 2nd pilot study in PaCa GEMMs showed that MRT was able to increase the tumor exposure of PEG-liposomal irinotecan (Onivyde®, FDA approved for PaCa treatment) and its active metabolite SN38 by >4-fold compared to Onivyde alone. This grant will allow us to translate our ground breaking MRT results to PaCa where the barriers to NP delivery are extensive, surgical resection is the only curative option but only 15% of patients have resectable disease and the MRT + NP regimen would be ideal for pre-surgical neoadjuvant treatment of PaCa. This work will be performed by a multidisciplinary research team using novel models, technologies and FDA approved drugs that can be readily translated to clinical trials in 3 aims over 5 yrs: AIM 1. Evaluate induction MRT-enhanced delivery of NP anticancer drugs in GEMMs of PaCa; AIM 2. Investigate mechanistic effects of induction MRT-enhanced tumor delivery of NPs in GEMMs of PaCa; AIM 3. Evaluate induction MRT-enhanced efficacy of NP anticancer drugs in GEMMs of PaCa. This proposal aims to overcome the inherent major barriers in NP delivery to tumors, especially in PaCa, which has significant barriers to drug tumor delivery.