Thesis or Dissertation Design of Quantum Dot-Based High Performance Nanoparticle Platform for Nanoparticle-Based Drug Delivery (NDD) system


Nanoparticle drug delivery (NDD) platforms have emerged as a promising approach to enhancethe efficacy of the existing drugs and potent therapeutic agents though encapsulation of poorlysoluble agents. However, the early design of NDD vehicles was governed by the intrinsicallypoor pharmacokinetic properties of conventional chemotherapeutics. Low drug solubility, rapidmetabolism and clearance, and most importantly a lack of selectivity regularly lead totherapeutic failure by causing severe systemic toxicity in healthy neighboring tissues, thusprohibiting the dose escalation necessary to eliminate tumor cells. Prime pre-requisite to asuccessful NDD is the ability to mediate the facile and efficient delivery of the nanoparticles tothe cell to ultimately deliver various drugs towards the target intracellular space and variousspecific subcellular compartments of mammalian cells. The traceability of the delivered drug isalso a crucial aspect in monitoring the biodistribution, intracellular trafficking, and long-termfate of drugs and NP-drug delivery vehicles in order to assess and characterize thepharmacokinetic properties as well as the targeting specificity of the delivered drug, which arelacking in the current NDD platforms. In this study, a novel strategy for the development ofhigh performance nanoparticle platform was established by means of cell surface mimeticquantum dots (QDs)-anchored peptides/glycopeptides as a model system for NDD vehicleswith defined functions facilitating intracellular trafficking after initial endocytosis.This study describes the standardized protocol for the preparation of multifunctional QDs thatallow for efficient cellular uptake and rapid escape from endolysosomal entrapment followedby subsequent molecular delivery to the target cellular compartment. The established protocoltook advantage of the facile chemoselective ligation of ketone-functionalized peptides andglycopeptides onto the surface of the aminooxy/phospholylcholine self-assembled monolayercoated QDs (AO/PCSAM-QDs) in mild reaction condition. Displaying ketone-functionalizedhexahistidine derivative onto the AO/PCSAM-QD surface during intracellular deliveryfacilitated both endocytic entry and rapid endolysosomal escape of the conjugates in varioushuman cell lines. Combined use of hexahistidylated AO/PCSAM-QDs with serglycin-likeglycopeptides, a proteoglycan initiators (PGIs), elicited an entry, controlled intracellulariiitrafficking, golgi localization and subsequent excretion of the QD conjugates, as also observedin the real-time live cell imaging. The results suggested that this approach can potentiallyprovide an ideal platform for the design of high performance NDD system that could trackevery stages of NDD.Therefore, it is noteworthy that PCSAM coating strategy could become a universal tool forspatially oriented immobilization of engineered proteins including antibody and antibody-drugconjugates on various metal-based nanoparticles.
xiii, 118p
Hokkaido University(北海道大学). 博士(生命科学)

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