Zhang, Peng
(2015)
RATIONAL DESIGN OF NANOCARRIERS WITH ENHANCED CARRIER-DRUG
INTERACTION FOR IMPROVED CANCER THERAPY.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Micelles are simple and effective nanocarriers in formulating hydrophobic agents. However, limited drug loading capacity and intrinsic poor formulation stability of micelles represent two major issues in the bench-to-bedside translation, which are largely attributed to the insufficient carrier-drug interaction. The aim of my dissertation study is to gain more insight into the molecular basis of carrier-drug interactions, and develop effective strategies to improve the compatibility of nanomicelles with chemotherapeutic agents for more efficient in vivo delivery.
Firstly, we demonstrated that introduction of additional mechanisms of carrier-drug interaction is an effective strategy to improve drug loading and stability of nanomicelles. We interfacially decorated micelle-forming PEG-lipids with Fmoc motifs that can effectively interact with drug molecules through π-π stacking and hydrogen bonding interactions. The resulting lipid vector showed dramatically enhanced effectiveness in formulating paclitaxel (PTX) and several other agents with diverse structures.
To clearly address the molecular basis of Fmoc/drug interaction, a new model was established by using a simple PEG-Fmoc conjugate without lipid chains. Interestingly, this system demonstrated a significant improvement in PTX encapsulation (36%, w/w). Our data indicated a strong Fmoc/PTX intermolecular π-π stacking, which may play a major role in the overall carrier-drug interaction, and high effectiveness of PEG-Fmoc in delivery of PTX to tumor cells in vitro and in vivo.
A further SAR study was conducted to investigate the impact of Fmoc neighboring group on the overall carrier-drug interactions. This study identified several factors that may impact the performance of micelles, which led to the discovery of Cbz as a favored neighboring group of Fmoc for effective interaction with a broad range of drugs. Based on this discovery, a nanocarrier with expanded interior volume was developed for co-delivery of multi-agents in combination chemotherapy. A dramatically enhanced anti-tumor activity over single agent therapy was achieved in both cultured cancer cells and tumor-bearing animal models.
In summary, incorporation of additional mechanisms of carrier-drug interactions significantly enhanced in vitro and in vivo performance of nanomicelles. Comprehensive SAR studies of carrier-drug interactions led to the discovery of several simple and effective nanocarriers for improved delivery of chemotherapeutic agents to tumors.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
17 September 2015 |
| Date Type: |
Publication |
| Defense Date: |
9 July 2015 |
| Approval Date: |
17 September 2015 |
| Submission Date: |
5 August 2015 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
163 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Drug delivery; nanocarrier; micelle; chemotherapy; carrier-drug interaction; Fmoc |
| Date Deposited: |
17 Sep 2015 17:27 |
| Last Modified: |
15 Nov 2016 14:29 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/25896 |
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