A polymer therapeutics and nanotechnology project is proposed, in which a phosphorylcholine vesicle (PCV) platform is designed and synthesized to improve the efficacy of cancer drugs. PCVs will benefit from the biocompatibility offered by the phosphorylcholine (PC) groups packed along the backbone, while serving as robust cancer drug carriers for in vivo therapeutics. The proposed Specific Aims will evaluate the key safety and efficacy aspects of PCVs, while advancing the fabrication of PCV polymers towards optimized structures. Optimization will stem from 1) choosing PCVs for initial in vivo evaluation based on their nanoscale size, drug loading, and ease of fabrication, and 2) using the results of in vivo experiments to adjust the size and functionality of PCVs towards enhancing key parameters in cancer drug delivery, such as maximum tolerated dose (MTD), pharmacokinetic (PK) profile, and efficacy in tumor xenograft models.
Specific Aim 1 evaluates PCVs in cell culture and animals, to obtain an understanding of MTD, PK, and efficacy, as well as toxicity and immunogenicity evaluation of PCV polymers themselves (i.e., without drug).
Specific Aim 2 embarks on PCV vesicle formation that extends the PCV platform into functional structures for further in vivo evaluation. The combined efforts of UMass Amherst PI Todd Emrick in polymer and vesicle preparation, BayState Medical Center co-investigator Sallie Schneider for in vivo cancer therapeutics, and BayState Medical Center consultant Dr. Richard Arenas will enable a thorough evaluation of the potential this novel drug delivery platform.

Public Health Relevance

Within the context of nanoscale therapeutics, a project is proposed to synthesize novel phosphorylcholine-based polymer vesicles (PCVs), and examine their safety and efficacy for in vivo cancer therapeutics. The proposed synthetic phosphorylcholine (PC)-functionalized polymers are novel and innovative, and have robust physical properties to prevent rapid deterioration in vivo and enable longer in vivo circulation time (preventing fast elimination). PCVs have the ability to encapsulate drugs in their interior, and carry drugs and/or targeting groups covalently on the vesicle wall. The project aims to provide chemotherapeutic treatment options that require less frequent dosing than can be achieved with conventional excipient and/or liposomal delivery, with reduced side-effects. Overall, the nanoscale size, stability, and functionality of PCVs offer great potential for a novel platform system.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA167674-01A1
Application #
8445725
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Fu, Yali
Project Start
2013-01-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
1
Fiscal Year
2013
Total Cost
$176,008
Indirect Cost
$65,311
Name
University of Massachusetts Amherst
Department
Engineering (All Types)
Type
Schools of Arts and Sciences
DUNS #
153926712
City
Amherst
State
MA
Country
United States
Zip Code
01003
McRae Page, Samantha; Henchey, Elizabeth; Chen, Xiangji et al. (2014) Efficacy of polyMPC-DOX prodrugs in 4T1 tumor-bearing mice. Mol Pharm 11:1715-20
McRae Page, Samantha; Martorella, Molly; Parelkar, Sangram et al. (2013) Disulfide Cross-Linked Phosphorylcholine Micelles for Triggered Release of Camptothecin. Mol Pharm :