Date of Award

2015

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Pharmaceutical Sciences

First Advisor

Wei Lu

Abstract

Cancer has become number one cause of death. Conventional treatment includes surgery, chemotherapy, radiation therapy, or combination. The combinatorial therapy in one system is highly efficient and economical. Herein, two drug delivery systems with chemo and photothermal therapy are developed in order to enhance the therapeutic efficacy in A549 human lung cancer cells. The first one is hollow copper sulfide nanoparticle carrying doxorubicin (PEG-HCuSNPs-DOX). The second one is mesoporous silica coated CuS nanoparticles (CuS NPs) loaded with doxorubicin (DOX) (PEG-CuS@MSNs-DOX).

Both nano-drug delivery systems are pH sensitive, laser responsive, and photothermal convertible. CuS NPs are the photothermal sensitizers in both drug delivery systems. However the drug loading efficiency is much higher in the PEG-CuS@MSNs-DOX, whereas its drug release rate is much slower. In addition, the anti-cancer efficacy of PEG-HCuSNPs-DOX is higher than that of PEG-CuS@MSNs-DOX.

Five chapters are prepared in this thesis. Each chapter includes an independent manuscript and separate abstract. Chapter 2 serves as preparation experiment for chapter 3. Chapter 4 is a review that expands the application of CuS NPs to transdermal delivery. Chapter 5 is a mini review on the in vivo application of CuS NPs

1. Cancer Photothermal Chemo Therapy Using Hollow Copper Sulfide Doxorubicin Nanoparticles The design and synthesis of the multifunctional nanoparticles responsive to external stimuli provides potential applications in biomedical fields such as controlled drug delivery. Here, near infrared (NIR) laser-controlled fast and effective tumor cell killing is achieved based on the pH sensitive and NIR light responsive hollow copper sulfide nanoparticles chelated with doxorubicin molecules (HCuSNPs-DOX). Laser exposure at 900 nm and acidic environment facilitate the release of DOX from HCuSNPs-DOX. Spontaneously, the released DOX forms DOX/Cu2+ complex and generates cell-killing reactive oxygen species. Laser exposure to HCuSNPs-DOX also disrupts the integrity of the cell membrane instantly. The IC50 of HCuSNPs-DOX with and without laser treatment was 4.0 and 7.6 μg/mL CuS, respectively. The approach developed here offers compelling chances for quick-responsive anticancer therapy.

2. Facile Direct Dry Grinding Synthesis of Monodisperse Lipophilic CuS Nanoparticles Copper sulfide with near-infrared light absorption property is recently attracting broad interest as a photothermal carrier for smart cancer therapy. Lipophilic copper sulfide nanoparticle is preferred for high performance biomedical applications due to the high affinity with tissues. But it requires complex multi-step synthetic process under severe condition. Here, synthesis of hydrophobic copper sulfide possessing surface plasmon resonance was retained by direct dry grinding of copper(II) acetylacetonate with sulfur under ambient environment. The formed CuS nanoparticles were in uniform size of ~10 nm, and they were monodispersed in pure chloroform. Each covellite CuS nanocrystal surface was modified with oleylamine through hydrogen bonding between sulfur atoms and amine groups of oleylamine. While those oleylamine capped CuS nanoparticles showed uniform morphological features, they demonstrated near-infrared light absorption for photothermal applications. The facile and mild synthetic methodology described here opened a powerful pathway for the design and preparation of photothermal lipophilic copper sulfide nanomaterials for smart cancer therapy.

3. Multifunctional Mesoporous Silica-Coated CuS Nanoparticles for Cancer Therapy: Synthesis, Characterization and in vitro Evaluation Chemo therapeutic drug-caused side effects are commonly seen in clinical practice due to nonspecific toxicity and low therapeutic efficiency. Herein, we reported a cancer chemo-photothermal multifunctional drug delivery system. Polyethylene glycol decorated mesoporous silica nanoparticles entrapping CuS nanoparticles (PEG-CuS@MSNs) were successfully synthesized and characterized for the drug delivery application. Doxorubicin (DOX)-loaded PEG-CuS@MSNs showed laser stimulated and pH-responsive properties. In vitro cell experiments demonstrated that DOX-loaded PEG-CuS@MSNs combining laser exposure achieved the highest rate of death of A549 cells, in comparison to that of PEG-CuS@MSNs-DOX chemotherapy alone. These findings provided a promising drug delivery system for cancer combinatorial therapy, which could significantly reduce drug dose and improve patient compliance.

4. Laser ablation-enhanced transdermal drug delivery Transdermal delivery offers an excellent route for drug and vaccine administration. Nonetheless, it presents a critical challenge due to the skin’s lipid-rich outer stratum corneum layer. Laser ablation perforates epidermis through selective photothermolysis, making skin more permeable to hydrophilic and macromolecular drugs such as peptides, proteins, and genes. This review summarizes recent applications to laser ablation-enhanced transdermal delivery. Needle- and pain-free transcutaneous drug delivery via laser ablation provides an alternative approach to achieve local or systemic therapeutics.

5. Cancer Photothermal Therapy and CuS Nanoparticles This manuscript is being prepared according to the format of Lasers in Medical Science as a review article.

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