Enhancement of in vitro therapeutic efficacy using combination paclitaxel and ceramide therapy using EGFR targeted biodegradable polymeric nanoparticles in ovarian cancer model

Title:
Enhancement of in vitro therapeutic efficacy using combination paclitaxel and ceramide therapy using EGFR targeted biodegradable polymeric nanoparticles in ovarian cancer model
Creator:
Patel, Darshna (Author)
Contributor:
Amiji, Mansoor M. (Advisor)
Gatley, Samuel (Committee member)
Mehta, Shashi (Committee member)
Publisher:
Boston, Massachusetts : Northeastern University, 2012
Date Accepted:
August 2012
Date Awarded:
May 2013
Type of resource:
Text
Genre:
Masters theses
Format:
electronic
Digital origin:
born digital
Abstract/Description:
Currently, tumor-cell resistance to the chemotherapy is key reason for failure of the clinical treatment of cancer cells; almost all chemotherapeutic strategies used are susceptible to multidrug resistance (MDR). The development of MDR is major hindrance to eradication of cancer as it interferes with the effect of therapeutic agents on tumors and increases chances of cancer resurgence.

MDR refers to a cross-resistance to structurally and functionally unrelated drugs thereby rendering the tumor unresponsive to most chemotherapeutic options. It results from microenvironmental selection, like poor delivery efficiency of drug at the disease site, phenotypic alterations in cancer cells leading to enhanced efflux of chemotherapeutic agents from cells, enhanced drug metabolism and alterations in apoptotic cascade pathway resulting in higher apoptotic threshold. Over-expression of membrane bound ATP-binding efflux pumps is the most implicated occurrence, but modulation of apoptosis pathway is another likely strategy for drug resistance.

Studies are done to observe relationship between levels of ceramide in cancer cells and progression of the tumors. Besides regulating normal biological functions like inflammatory responses and cell proliferation, it is also implicated in programmed cell death and cell senescence. Multiple antineoplastic drugs have been shown to increase intracellular ceramide levels prior the induction of apoptosis. So increasing intracellular ceramide concentration can be approached as a novel mode of treating MDR. Ceramides are synthesized exogenously and different formulation systems, like liposomes and nanoparticles, have been developed for their delivery. The major advantage of ceramide is, as an endogenous compound, ceramide is not bound to show any toxicity in normal cells. But the down side is, it is also susceptible to endogenous enzymes like ceramidase.

Short-chain cell permeable ceramides, such as C6 ceramide, has antiproliferative and pro-apoptotic activity. As the main site of apoptotic action of ceramide is mitochondria, it is hypothesized that mitochondrial derivatives of ceramide would be more effective in comparison to the parent ceramide compound. The delivery of ceramide for cancer chemotherapy is associated with problems, such as limited permeability and possible precipitation when administered as aqueous solution, due to the hydrophobicity and metabolic inactivation of the circulating free form of ceramide. To overcome these problems, formation of nanoparticles using long chain biodegradable polymers (PCL and PLGA) is suggested. The later can be attached to an EGFR peptide so as to target the cancer cells specifically. Since the pro-apoptotic activity of ceramides has been shown to be in the mitochondria, we hypothesize that mitochondria-targeted ceramide would be significantly more potent in lowering the tumor apoptotic threshold in MDR.

In order to enhance delivery efficiency of combination paclitaxel (PTX), a cytotoxic chemotherapeutic agent, and ceramide, biodegradable polymeric nanoparticles that can target the epidermal growth factor receptors (EGFR) over-expressed on many tumor cells were engineered, including SKOV3 human ovarian adenocarcinoma cells. Ceramide was encapsulated in non-targeted poly(ethylene glycol) (PEG)-PLGA/PCL blend nanoparticles and EGFR-targeted peptide-PEG-PLGA/PCL blend nanoparticles. PTX/CER combination therapy was evaluated in SKOV3 wild-type cells.

The preliminary studies show that we can formulate the blend nanoparticles for single and combination therapy and delivery of ceramide using nanoparticle formulation was significantly more effective than free drug in solution. Further studies were carried out to develop EGFR-targeted nanoparticles and evaluate intracellular delivery of ceramide along with PTX and evaluate pro-apoptotic activity and cytotoxicity in SKOV3 wild-type cells.
Subjects and keywords:
biodegradable nanoparticles
ceramide
drug resistance
ovarian cancer
paclitaxel
tumor targeting
Medicinal and Pharmaceutical Chemistry
Pharmaceutics and Drug Design
Pharmacy and Pharmaceutical Sciences
DOI:
https://doi.org/10.17760/d20002956
Permanent Link:
http://hdl.handle.net/2047/d20002956
Use and reproduction:
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