Enhancement of Drug Delivery Efficiency via Nanotechnologies

Abstract

Nanotechnology is rapidly developing subdivision of technology that can be applied in many fields. With nanotechnology, more efficient drugs for diseases, more useful devices and better materials for diagnosis will be developed. In this thesis, we mainly focus on the diamond nanoneedle arrays and nanomedicines in the field of drug delivery in cancer treatment and the mechanism under this high delivering efficiency.

First, we investigate the physical approach to successfully deliver various drugs into different cancer cell line, including cancer resistant cells line. Due to the unique characteristics of being simple, efficient, high-throughput, safe and cost-effective, vertically aligned nanostructure arrays are now attracting tremendous attention in field of diagnosis and drug delivery. Particularly, we create diamond nanoneedle arrays because diamond possesses extremely strong mechanical properties and unprecedented biocompatibility. The device is applied to actively and directly disrupt cell membranes under precisely controllable centrifugation force and therefore greatly facilitate the delivery of different biomaterials into cytoplasm of cells. Furthermore, we also investigate the potential influence of this device on cell physiology, including cell membrane, disturbance on DNA double strands, reactive oxygen species (ROS) contents, mitochondrial membrane potential, etc. Although the treatment of diamond nanoneedle arrays could not induce cells death directly, the treatment indeed disrupts the cell membrane and cytoplasmic redox environment. Our study provides a novel understand on cytosolic delivery mediated by nanoneedle arrays and bridges new materials and basic biology at the same time.

Second, we synthesize carrier-free, pure drug nanoparticles for enhancing drug delivery efficiency. In previous reports, hydrophobic drugs are usually delivered with the assistant of carriers, nevertheless, the drug loading capacity in the nanocarrier-based system is usually low and the presence of carriers may increase the burden and potential toxicity in body. In our report, we synthesize carrier-free, cisplatin nanoparticles to enhance the drug delivery efficacy without the assistant of other agents or carriers. Furthermore, we also utilize rapamycin for enhancing the sensitivity to cisplatin in cancer cells. It is believed that the nanoparticles of drug molecules not only can enhance the delivering efficacy, but also can increase the cytotoxicity meanwhile. With the assistant of pH sensitive polymer PSMA, cisplatin nanoparticles can be coupled with a series of bio-fluorescent molecules, such as fluorescein isothiocyanate (FITC) and Cy5, thus the behavior of drug nanoparticles can be monitored in time. The unique structure of PSMA can also be utilized to adsorb other anti-cancer drugs via the π-π interaction. Further application of this system needs to be investigated in our future work.

Thirdly, in the thesis, we also investigated the combined treatment of photodynamic treatment and chemotherapy based on the ultra-thin layered double hydroxide (LDH) delivering system. Ce6 and SN38 are employed in this study. The LDH-Ce6/SN38 hybrid nanocomposites exhibit significant higher cytotoxicity than individual drugs in the same dose. Meanwhile, intratumoral injection of LDH-Ce6/SN38 hybrid nanocomposites also displays a synergetic therapeutic effect and possesses superior tumor ablating ability in vivo treatment without inducing significant body weight loss. Further results of H&E staining reveal no apparent toxicity of LDH-Ce6/SN38 hybrid nanosheets to mice at our treated dose within two weeks.

We also investigated the synergistic therapy by combining photothermal agent with chemotherapeutic drug. By controlling the temperature around an appropriate range, the sensitivity of cancer cells to chemotherapeutic drugs can be increased. Previous work has already demonstrated light-to-heat property of PEDOT: PSS with strong absorbing in near-infrared range, the PEDOT: PSS was assembled together with doxorubicin (DOX) and coated with charged polymers via layer-by-layer method, and conjugated with polyethylene glycol for in vivo experiment at last. The obtained PEDOT: PSS/DOX-PEG (PPD-PEG) nanoparticles, exhibited higher light-to-heat ability than PEDOT: PSS and stronger cytotoxicity than single dugs at the same dose. Further experiments for in vivo cancer treatment also displayed the excellent tumor killing property, while no apparent toxicity was observed as shown in the body weight curve and histological examination.

In summary, on one hand, we improved the drug delivery efficacy by physically penetrating cell membrane with diamond nanoneedles, and investigated the physiological mechanism during this treatment. On the other hand, we developed the synergistic therapy with different materials and chemotherapeutic drugs. These results will benefit the development of nanomedicine and clinical treatment for cancer therapy in the future.