Protease-Sensitive Liposomes in Chemotherapy & Chemoradiotherapy: From Material Development to In Vivo Application in Tumor-Bearing Mice

Rikke Yding Brogaard

    Research output: Book/ReportPh.D. thesisResearch

    Abstract

    Chemotherapeutics is one of the most common treatments for cancer. Even so, systemic toxicity frequently requires a dose reduction to limit side effects, which subsequently limits the efficacy of the therapy. Nanomedicine is an effective strategy that can reduce side effects and enhance the therapeutic efficacy of the chemotherapeutic agents. However, availability of the drug payload after tumor accumulation remains a general challenge in many existing drug delivery systems (DDS). Designing DDSs that provide release of the drug payload in a controlled fashion is therefore of great importance to enhance therapeutic efficacies.
    In this thesis, the development, characterization, and evaluation of an advanced liposomal DDS and its potential in chemoradiotherapy is presented from material development to in vivo application in tumor*bearing mice.
    In the first part of the thesis, we report the design of a matrix metalloproteinase (MMP)* sensitive liposomal DDS, wherein local expression of MMPs in the tumor microenvironment converts a PEGylated anionic liposome into a dePEGylated cationic liposome, which is readily internalized by cells. Specifically, we demonstrate the enzyme*mediated charge reversal concept of the liposomal
    DDS, which leads to rapid cellular uptake. Various lipid compositions are tested in uptake and cytotoxicity experiments in vitro, followed by in vivo experiments where the ability of the liposomal DDS to accumulate in tumors together with its anti*cancer activity is explored in tumor*bearing mice. The in vivo data demonstrates superior anti*cancer activity relative to the free drug and to conventional, long circulating liposomes. This indicates that the MMP*sensitive
    liposomal DDS holds potential in therapeutic applications.
    In the second part of the thesis, the potential impact that the liposomal DDS employs in chemoradiotherapy is explored. Here, the liposomal DDS is evaluated as the chemotherapeutic agent in chemoradiotherapy with the aim of enhancing the outcome of radiotherapy. In vivo, the combinatorial treatment with the liposomal DDS and radiation showed a significantly higher anti*cancer effect than any of the monotherapies as well as the combinatorial treatment of the free
    drug and radiation. Furthermore, evaluation of tumor tissues indicated that the platinum* DNA chelation in tumor tissues correlated with the observed anti*cancer effects. Finally, we anticipate that the findings in this thesis will lead to future studies with the liposomal DDS and reveal some of the mechanistical uncertainties.
    Original languageEnglish
    PublisherDTU Nanotech
    Number of pages138
    Publication statusPublished - 2017

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