Performing Department
Chemistry
Non Technical Summary
Drug delivery systems can be used to increase a drug's circulatory stability and thereby raise theprobability for passive accumulation within regions of enhanced permeability, particularly tumor tissue.As a result, exposure of healthy tissue to associated therapeutics is limited, while therapeutic efficacy ismaximized. Both the specificity and therapeutic efficacy of drug delivery systems can be furtherimproved by combination with an active targeting moiety that is specific for receptors concentrated at thediseased site. Despite demonstrated success at increasing the efficacy and reducing the adverse impact ofanti-cancer therapeutics, translation of carrier systems to a clinical setting has been hampered by the useof materials that are not sufficiently biodegradable and biocompatible. Furthermore, the existing drugdelivery systems can be difficult to prepare and are often not readily amenable to functionalization. In thisproposal, use of bacteria-produced, environmentally friendly polymers, poly(3-hydroxy-octanoate-co- l 0-undecenoates (PHOUs), with high biodegradability and inherent biocompatibility, as the basis of atailorable drug delivery system for the treatment of metastatic breast cancer will be explored. The PHOUpolymers will possess terminal alkene groups that will be readily functionalized through thiol-ene clickchemistry for active targeting. The approach will demonstrate that biocompatible, actively targetednanopmticles can be prepared from bacteria-produced PHOU polymers and that these PHOUnanoparticles can be used to delive1y anti-cancer therapeutics to cancer cells.
Animal Health Component
(N/A)
Research Effort Categories
Basic
100%
Applied
(N/A)
Developmental
(N/A)
Goals / Objectives
The goal of this proposal is to develop tailorable nanocarriers for site-specific drug delivery frompolyhydroxyalkanoate (PHA) polymers, a class of stereospecific polyesters produced by bacteria.
Project Methods
1. Prepare biocompatible, cancertargetednanoparticles from bacteriaproducedPHOUs. After bacterialsynthesis of PHOU with control of 10-undecenoate content, the terminal vinylgroups will be reacted with a thiolfunctionalizedtargeting agent (folate orpeptide) via thiol-ene click chemistry toimprove selectivity for cancer tissue.Nanoparticles will be formulated from thefunctionalized PHOU viananoprecipitation. The biocompatibility ofthe PHOU nanoparticles alone will be evaluated in vitro in cultures of metastatic cancer cell lines.2. Evaluate the capacity of the targeted PHOU nanoparticles to encapsulate and deliver existing anticancertherapeutics. Paclitaxel (PTX) will be used as a model chemotherapeutic for encapsulation withinthe PHOU nanoparticles. In vitro models based on metastatic cancer cell lines will be used to assess thecytotoxic/antiproliferative effect of free PTX and PTX-loaded nanoparticles, while in vivo mouse modelswill be used to evaluate biodistribution and safety.