Nanoparticles (NPs) have been widely pursued as a promising tool to increase the biodistribution of an- ti-cancer therapeutics in tumors, thereby reducing the general exposure to chemotherapy. It is generally acknowledged that defective vasculature and lymphatic systems surrounding tumors offer a selective oppor- tunity for NPs to accumulate in tumors. However, the amount delivered to tumors this way is only a small frac- tion (~5%) of the total administered NPs. This challenge may be addressed by decorating the surface of NPs using a tumor-specific ligand, but the benefit is often limited due to the heterogeneity and genetic instability of tumors. Challenges in drug delivery using NPs are aggravated by the limited penetration of NPs into tumors, due to high tissue stiffness and interstitial fluid pressure. Substantive departure from the status quo NP-based drug delivery requires a new strategy to increase the amount of NPs delivered to and retained by tumors beyond the level currently possible based on passive delivery via the so-called enhanced permeability and retention (EPR) effect or other targeting strategies. Our long term goal is to develop a new drug delivery strategy that enhances delivery of nanomedicine into solid tumors to a greater extent than currently achieved. The objective of this application is to enhance the accumulation, retention, and penetration of anti-cancer drugs into solid tumors, via synergistic application of environmentally-adaptive NPs (ENPs) and image-guided radiation-induced permeability (IGRIP). Our central hypothesis is that NPs developing cationic surface or reduced size specifically in tumors will be better retained and/or penetrated in tumors than conventional non-adaptive NPs, and tumor accumulation of such NPs will be actively increased by targeted irradiation that results in local increase of microvascular permeability. The ra- tionale for this project is that its successful completion will enable the delivery of a greater amount of anti- cancer therapeutics to solid tumors than currently achieved with existing technology, thereby enhancing the effectiveness of cancer therapy. We will achieve our objective by pursuing the following three specific aims, where we will optimize the synthesis of ENPs and encapsulation of a model anti-cancer drug, paclitaxel (PTX) (Aim 1) and validate the IGRIP effect in a mouse model of prostate cancer (PCa) and optimize the irradiation regimen for NP delivery (Aim 2). Based on the optimized ENPs and irradiation regimen, we will correlate the pharmacokinetics and biodistribution of PTX delivery and anti-tumor effects in mice with PCa, to test the effec- tiveness of ENPs in PTX delivery to tumors as compared to Abraxane and the IGRIP enhancement of ENP delivery (Aim 3). By the completion of this study, we expect to have confirmed our approach as a valid meth- odology to increase biodistribution of nanomedicine into solid tumors and enhance therapeutic potential.
The proposed research is relevant to public health because a drug delivery strategy that increases deposition of nanomedicine in tumors to a greater extent than currently possible can enhance the efficacy of chemotherapy, minimize systemic side effects, prolong patient survival and improve their quality of life. There- fore, this research is consistent with the mission of the NIH, which pertains to developing resources that will assure the Nation's capability to efficiently prevent and/or treat human diseases.
|Hyun, Hyesun; Park, Joonyoung; Willis, Kiela et al. (2018) Surface modification of polymer nanoparticles with native albumin for enhancing drug delivery to solid tumors. Biomaterials 180:206-224|
|Appelbe, Oliver K; Kim, Bieong-Kil; Rymut, Nick et al. (2018) Radiation-enhanced delivery of plasmid DNA to tumors utilizing a novel PEI polyplex. Cancer Gene Ther 25:196-206|
|Xu, Jun; Lee, Steve Seung-Young; Seo, Howon et al. (2018) Quinic Acid-Conjugated Nanoparticles Enhance Drug Delivery to Solid Tumors via Interactions with Endothelial Selectins. Small 14:e1803601|
|Meng, Fanfei; Wang, Jianping; Ping, Qineng et al. (2018) Quantitative Assessment of Nanoparticle Biodistribution by Fluorescence Imaging, Revisited. ACS Nano 12:6458-6468|
|Gad, Sheryhan F; Park, Joonyoung; Park, Ji Eun et al. (2018) Enhancing Docetaxel Delivery to Multidrug-Resistant Cancer Cells with Albumin-Coated Nanocrystals. Mol Pharm :|
|Liu, Yuanfen; Tamam, Hassan; Yeo, Yoon (2018) Mixed Liposome Approach for Ratiometric and Sequential Delivery of Paclitaxel and Gemcitabine. AAPS PharmSciTech 19:693-699|
|Park, Joonyoung; Park, Ji Eun; Hedrick, Victoria E et al. (2018) A Comparative In Vivo Study of Albumin-Coated Paclitaxel Nanocrystals and Abraxane. Small 14:e1703670|
|Han, Ning; Pang, Liang; Xu, Jun et al. (2017) Development of Surface-Variable Polymeric Nanoparticles for Drug Delivery to Tumors. Mol Pharm 14:1538-1547|
|Appelbe, Oliver K; Moynihan, Kelly D; Flor, Amy et al. (2017) Radiation-enhanced delivery of systemically administered amphiphilic-CpG oligodeoxynucleotide. J Control Release 266:248-255|
|Meng, Fanfei; Han, Ning; Yeo, Yoon (2017) Organic nanoparticle systems for spatiotemporal control of multimodal chemotherapy. Expert Opin Drug Deliv 14:427-446|
Showing the most recent 10 out of 26 publications