Evaluational studies of a near-infrared triggered liposome-based photodynamic therapy of cancer.

摘要

This dissertation is based on developing the framework for evaluation of a theranostic liposomal delivery platform for indocyanine green (ICG) as the photosensitizer in a photodynamic therapy (PDT) of Triple Negative Breast Cancer (TNBC). Due to poor prognosis, short-term metastases, chemoresistance and lack of targeted therapies, TNBCs were evaluated based on the necessity for expansion of treatment modalities. The preliminary section following the introductory chapter describes the in vitro experiments to evaluate the effects of free ICG (FRICG) and liposome-loaded ICG (LPICG) across a panel of TNBC cell lines. Cytotoxicity profiling, clonogenic assessment, and DNA double strand break damage results demonstrate treatment effectiveness in inhibiting tumor cell growth of several TNBC cell lines.;The next section describes the expansion of the previous study for in vivo evaluation of LPICG-based PDT using a human TNBC xenograft model in nude mice. The primary focus was to determine the feasibility of the treatment evaluating multiple factors that directly influence tolerability and efficacy. Near-infrared (NIR) irradiation induced temperature effects, quantitative pharmacokinetic profiles, fluorescence imaging-based biodistribution patterns, and anti-tumor efficacy for both FRICG and LPICG were determined. Results demonstrated a significant temperature rise in tumors during treatment, which correlated with the previous in vitro studies. The pharmacokinetics evaluation revealed a significant increase in systemic distribution and circulation half-life of LPICG. Finally, NIR-mediated imaging demonstrated enhanced accumulation of LPICG within tumors. Ultimately tumor growth in mice using LPICG was significantly reduced compared to control groups.;The final chapter discusses the potential for synergism of PDT in combination with poly (ADP-ribose) polymerase 1 (PARP1) inhibition using Olaparib. For the combinational treatment, cytotoxicity was evaluated using Olaparib to sensitize cells prior to PDT. Treatment interactions were defined by combination index values. Results demonstrated treatment potentiation by a synergistic outcome using Olaparib combined with PDT. Taken together, this dissertation describes critical details towards better understanding of the effects of modern light therapy via LPICG-based PDT. The agreement and correlation between the in vitro and in vivo studies illustrate a unique and promising approach for further exploration in personalized medicine as modern emerging non-invasive cancer therapies.