Polymer micelles have been used widely for delivery of poorly water-soluble drugs. Despite their promising properties, they have not been fully developed as a vehicle for target delivery of anticancer agents. This is mainly due to the lack of understanding on the in vivo behavior of polymer micelles upon intravenous administration. Physically self-assembled polymer micelles are not expected to be stable in blood, and yet, no systematic studies have been made. This study is focused on understanding the interactions between polymer micelles and blood components for development of a new class of polymer micelles for targeted delivery of anticancer agents for clinical applications. The long-term goal of this research is to develop adaptable polymer micelles that are stable in blood but undergo dissociation by enzymes abundant at the tumor site. The hypothesis in this project is that the stability of polymer micelles in blood is prerequisite for successful tumor therapy. Only the stable polymer micelles have chances to target tumors and deliver anti-tumoral drugs at the therapeutically effective level.
Specific Aims of this project are: (1) to develop adaptable polymer micelles;(2) to examine the micelle stability in blood;(3) to elucidate the micelle-cell interactions;and (4) to characterize the in vivo fate of micelles and to study the anti-tumoral activity of drug-loaded micelles. The two drugs to be used for tumor therapy are paclitaxel and gefitinib, which have similar hydrophobicity. The synergistic effect of the two-drug pair is expected, resulting in substantially better anti-tumoral effect. The adaptable polymer micelles will be prepared by crosslinking the hydrophobic core of the micelles through disulfide or peptides that are degradable by thrombin or matrix metalloproteinase 2 (MMP2) which are abundant at the tumor sites. The blood stability and tumor targeting properties of the adaptable polymer micelles will be examined by coherent anti-Stokes Raman scattering (CARS), fluorescence reflectance imaging (FRI), and fluorescence molecular tomography (FMT). The results of in vitro and in vivo experiments will be used to improve the properties of the adaptable polymer micelles, and such feedback cycle will be repeated to produce the optimal polymer micelles. The significance of our proposed research is that it will elucidate the factors affecting the stability of polymer micelles in blood, as well as cellular uptake, and in vivo fate/behavior of the micelles. Successful completion of this project is expected to produce adaptable polymer micelles that are effective for targeted delivery of a two-drug pair to the tumor sites.

Public Health Relevance

The goal of this project is to develop a new type of polymer micelles that are stable in blood but undergo structural changes by enzymes abundant at the tumor site (i.e., adaptable polymer micelles) for targeted delivery of anticancer agents to the tumor site via intravenous injection.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA129287-04
Application #
8391233
Study Section
Gene and Drug Delivery Systems Study Section (GDD)
Program Officer
Tandon, Pushpa
Project Start
2009-12-15
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
4
Fiscal Year
2013
Total Cost
$281,401
Indirect Cost
$92,202
Name
Purdue University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907
Lee, Byung Kook; Yun, Yeonhee; Park, Kinam (2016) PLA micro- and nano-particles. Adv Drug Deliv Rev 107:176-191
Han, Bumsoo; Qu, Chunjing; Park, Kinam et al. (2016) Recapitulation of complex transport and action of drugs at the tumor microenvironment using tumor-microenvironment-on-chip. Cancer Lett 380:319-29
Park, Kinam (2015) Drug delivery of the future: Chasing the invisible gorilla. J Control Release :
Lee, Steve Seung-Young; Li, Junjie; Tai, Jien Nee et al. (2015) Avasimibe encapsulated in human serum albumin blocks cholesterol esterification for selective cancer treatment. ACS Nano 9:2420-32
Yun, Yeon Hee; Lee, Byung Kook; Park, Kinam (2015) Controlled Drug Delivery: Historical perspective for the next generation. J Control Release 219:2-7
Lee, Byung Kook; Yun, Yeon Hee; Park, Kinam (2015) Smart Nanoparticles for Drug Delivery: Boundaries and Opportunities. Chem Eng Sci 125:158-164
Lu, Ying; Wang, Zhao-hui; Li, Tonglei et al. (2014) Development and evaluation of transferrin-stabilized paclitaxel nanocrystal formulation. J Control Release 176:76-85
Park, Kinam (2014) Controlled drug delivery systems: past forward and future back. J Control Release 190:3-8
Kwak, Bongseop; Ozcelikkale, Altug; Shin, Crystal S et al. (2014) Simulation of complex transport of nanoparticles around a tumor using tumor-microenvironment-on-chip. J Control Release 194:157-67
Wu, Wei; Lee, Seung-Young; Wu, Xiangbing et al. (2014) Neuroprotective ferulic acid (FA)-glycol chitosan (GC) nanoparticles for functional restoration of traumatically injured spinal cord. Biomaterials 35:2355-64

Showing the most recent 10 out of 23 publications