Advisor(s)

Vladimir P.Torchilin

Contributor(s)

Robert Campbell, Kim Lewis, Robert A. Schatz, Volkmar Weissig

Date of Award

2008

Date Accepted

11-13-2008

Degree Grantor

Northeastern University

Degree Level

Ph.D.

Degree Name

Doctor of Philosophy

Department or Academic Unit

Bouvé College of Health Sciences. School of Pharmacy.

Keywords

Health science, Drug delivery systems, Nanotechnology

Subject Categories

Polymeric drug delivery systems, Drug delivery systems

Disciplines

Pharmacy and Pharmaceutical Sciences

Abstract

The undesired side-effects of many therapies and diagnostics result from their accumulation in the non-target tissues. There is a clear need to design pharmaceutical delivery systems capable of delivering drugs, DNA and diagnostics to the target tissue with minimal accumulation in the non-target tissues. Targeted delivery of pharmaceuticals will help in reducing accumulation and undesired side-effects in the non-target organs, and increase the amount of drug delivered and drug bioavailability at intended target organs. Targeting can be achieved passively by long circulation time of the pharmaceuticals in the blood, actively by using target-specific ligands or by combination of both. The major long term goal of this project is to develop optimal delivery systems capable of delivering drugs, DNA or imaging agents to the intended target site using polymeric carriers like dextran, or nanoparticulate carriers like liposomes and micelles. In this study, polyethylene glycol (PEG), a biocompatible hydrophilic polymer was used as the key component of various delivery systems to make them long-circulating for passive targeting and/or actively targeted via the attachment of various ligands onto their surfaces. PEG conjugates have been used to modify existing delivery platforms like dextran, to increase its circulation time in blood. PEG-phosphatidylethanolamine (PEG-PE) conjugates spontaneously form micelles with a hydrophobic lipid core to entrap super-paramagnetic iron oxide nanoparticles (SPION) and form stable nano-sized suspensions of SPION-micelles. There was a significant improvement in MRI signal from the SPION-micelles compared to ""plain"" SPION. To prepare targeted contrast agents, para-nitrophenyl PEG-PE (pNP-PEG-PE) conjugates were used to surface-modify SPION-micelles with the anti-cancer nucleosome-specific monoclonal antibody 2C5 (mAb2C5). mAb2C5-SPION-micelles demonstrated increased association with cancer cells and were able to bring more MRI contrast signal to cancer cells in vitro. Moreover, physical targeting of SPION-micelles into subcutaneous tumor models in mice in vivo was also possible by using an external magnet. Stimuli (pH)- sensitive PEG-PE conjugates [with a pH-cleavable hydrazone bond between PEG and PE (PEG-Hz-PE) making PEG detachable from the conjugate at lowered pH] can be used to prepare multifunctional nanocarriers with ""hidden"" functions that will be developed only upon external stimuli (lowered-pH values in tumor interstitium). Cell-penetrating peptides (CPPs) have been shown to effectively deliver the cargoes into the cell. Using pH-sensitive PEG-Hz-PE, we have constructed multifunctional nanocarriers which, in addition to prolonged circulation (via the attached PEG) and target recognition (via the attached antibody), carry the temporarily hidden CPP function. The CPPs attached to the nanocarriers are ""shielded"" with PEG chains under normal pH values (as in blood), however upon the incubation at low-pH values, hydrazone bond hydrolyzes, PEG detaches, and the CPPs become exposed and help internalize the nanocarriers into the cells. This is a significant step on the way toward ""smart"" multifunctional pharmaceutical nanocarriers capable of both target accumulation and intracellular penetration in a controlled fashion.

Document Type

Dissertation

Rights Holder

Rishikesh Manohar Sawant


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