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Nanocarrier system for overcoming multidrug resistance in cancer

dc.contributor.advisorLamprecht, Alf
dc.contributor.authorSingh, Manu Smriti
dc.description.abstractOf all the cases, majority of cancer patients respond to therapeutic interventions transiently or incompletely. These multidrug resistant (MDR) cancer cases are either resistant to chemotherapy or acquire resistance during treatment. Overcoming MDR in cancer is a major challenge to clinicians and researchers alike. Transporter proteins of the ATP-binding cassette (ABC) superfamily are over-expressed on membranes of MDR cancer cells and are responsible for effluxing anti-cancer drugs. Amongst the ABC transporters identified from prokaryotes to humans- P-glycoprotein (P-gp), multidrug resistance-associated protein-1 (MRP1) and breast cancer resistance protein (BCRP) are the most characterized phenotypes that confer drug resistance.
An interesting phenomenon has been the emergence of routinely used pharmaceutical excipients (surface active agents) such as surfactants, poloxamers, PEG derivatives and their analogues as MDR modulators. The first chapter highlights inclusion of these approved ‘Generally Recognized As Safe’ pharmaceutical excipients in different class of nanocarriers.
Nanoparticles offer promise as drug delivery systems mainly due to the fact that they prevent recognition of drugs by efflux pumps present on cell membrane and improve drug accumulation at the tumor site; thereby, reducing systemic side effects or pharmacokinetic profiles of therapeutic molecules leading to killing of drug resistant tumor cells. The current arsenal of nano-sized formulations comprise of liposomes, solid-lipid nanoparticles or polymeric micelles etc., which have been developed to carry anti-cancer drugs and/ or inhibitor or a combination thereof with the sole aim of reversing MDR in cancer.
In first part of this work, we formulated nanoparticles using different excipients. The aim was to develop nanoparticles with inherent ‘surface active’ properties (devoid of MDR inhibitor), which following their interaction with cell membrane would modulate P-gp function so as to facilitate substrate entry. The effect of excipient-based nanoparticles was evaluated on highly drug resistant P-gp over-expressing brain tumor cell lines.
Different generations of ABC inhibitors have proved disappointing due to ineffective inhibition of efflux transporters, inherent toxicity and low availability at tumor site. It is increasingly important to prevent pharmacokinetic and pharmacodynamic interactions between anti-cancer drug and MDR inhibitors and the resultant systemic toxicity of latter. Encapsulating MDR inhibitor in nanoparticles not only improves their intra-tumoral accumulation profile, it also prolongs inhibitor release which can lead to sustained and efficient sensitization of drug resistant cells towards anti-cancer drug. In the second set of this work, inhibitor-loaded nanoparticles were investigated.
In this part, we further wanted to evaluate the effect of surface charge on the properties of MDR inhibitor-loaded nanoparticles in drug resistant and drug sensitive cell lines. Hence, first and third-generation P-gp inhibitors- verapamil hydrochloride and elacridar were encapsulated in non-ionic, cationic and anionic nanoparticles and assessed for their ability to reverse cancer drug resistance. Mechanism of endocytosis of nanoparticles in both cell lines were also investigated by using different pharmacological inhibitors.
Two recently synthesized quinazoline compounds- KCJ-160 and KCJ-199, both exhibiting inhibition of BCRP and to a lesser extent of P-gp have been identified. In the last part of my work, both broad spectrum MDR inhibitors were formulated in nanocarriers and assessed in comparison to their soluble counterparts for their potency to overcome P-gp and BCRP mediated drug resistance in relevant cell line models.
dc.rightsIn Copyright
dc.subject.ddc615 Pharmakologie, Therapeutik
dc.titleNanocarrier system for overcoming multidrug resistance in cancer
dc.typeDissertation oder Habilitation
dc.publisher.nameUniversitäts- und Landesbibliothek Bonn
ulbbnediss.affiliation.nameRheinische Friedrich-Wilhelms-Universität Bonn
ulbbnediss.instituteMathematisch-Naturwissenschaftliche Fakultät : Fachgruppe Pharmazie / Pharmazeutisches Institut/Pharmazeutische Technologie
ulbbnediss.fakultaetMathematisch-Naturwissenschaftliche Fakultät
dc.contributor.coRefereeWagner, Karl Gerhard

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