The Role Of Nanomaterials In Cancer Therapy

Inefficient tumor cell killing and drug resistance are among the major problems hampering the efficacy of cancer chemotherapy. Autophagy, an evolutionally-conserved intracellular degradation process involving lysosomes, influences the response of tumor cells to chemotherapeutic treatment. Fullerene C60 has been shown to induce certain static features of autophagy, but no detailed studies have been undertaken. In part 1 we show that Nano-C60, the nanocrystal of fullerene C60 stably dispersed in water, induced abberant autophagy with increased autophagosome formation and reduced autophagic turnover in a photo-enhanced and free radical-dependent fashion. The autophagy-inducing dose of Nano-C60 did not directly cause cell death but sensitized chemotherapeutic killing of normal as well as drug-resistant cancer cells, in a process that requires a functional Atg5, an autophagy-essential gene. Our results revealed for the first time a novel biological function for Nano-C60 in enhancing the cytotoxicity of chemotherapeutic agents and reducing drug resistance through autophagy modulation and may point to the potential application of Nano-C60 in adjunct chemotherapy. Poly(amidoamine) (PAMAM) dendrimers are a class of artificial macro-molecules with tree-like structure. They are hyperbranched, monodisperse, three-dimensional molecules with well-defined shapes, molecular weights, sizes, branched layers, hydrophobic pockets, and surface functionalities. Star-burst dendrimers represent a superior carrier platform for targeted drug delivery. In this part of we explore the application of PAMAM dendrimers as cancer-targeting devie and drug carriers.The interactions between PAMAM dendrimers and drugs are also investigated.This part of the dissertation comprises four chapters. Chapter 1 begins with a summary on dendrimer and its applications in biomedicine especially PAMAM dendrimers.In charpter 2 of this part, polymeric nano-carriers based on PAMAM dendrimers and biotin molecules are synthesized for cancer targeting therapy and diagnosis. As revealed by flow cytometry and confocal microscopy, the dendrimer-biotin conjugate exhibits exhibited much higher cellular uptake into cancer cells than the conjugate without biotin. The uptake was energy-dependent, dose-dependent, and could be effectively blocked by dendrimer-conjugated biotin. The results indicated that the biocompatible biotin-dendrimer conjugate might be a promising nano-platform for cancer therapy and cancer diagnosis.In chapter 3 we report the encapsulation efficiency of a PAMAM dendrimer employing antileukemic drug 6-mercaptopurine. A frequent problem encountered with conventional chemotherapy is the lack of appreciable water solubility exhibited by the cytotoxic agent.MacromoIecular carriers can be used to augment the solubility of such drugs .Of such macromolecular systems emerge a class of spherical, hyper-branched polymers known as dendrimers. Our investigation have found that the encapsulation efficiency of a PAMAM dendrimer bearing amino- terminal groups can encapsulate the poor water solubility antileukemic drug 6-mercaptopurine and enhance its solubility . It was found that under alkaline conditions (pH=10), encapsulation of the drug was the highest. However, under acidic conditions, the encapsulation of the drug was slightly lowered. We also find the concentration of salt has no effect on the encapsulation efficiency.In Chapter 4 the interactions between PAMAM dendrimers and the non-steroidal anti-inflammatory drug phenylbutazone are investigated. Solubility results showed that PAMAM dendrimers significantly enhanced the aqueous solubility of phenylbutazone and the solubilization was much influenced by dendrimer concentration, generation, surface function group and pH value. The 2D-NOESY spectra clearly showed that there were several kinds of cross-peaks from NOE interactions between the protons of phenylbutazone and the protons in interior cavities of both generation 6 and generation 3 PAMAM dendrimers. Evidence from the solubility, 2D-NOESY results and ITC analysis suggest that encapsulation and electrostatic interaction together caused the solubility enhancement of phenylbutazone. The new techniques such as two-dimensional NMR and Isothermal Titration Calorimetry techniques used in this study are useful tools in investigating the interactions between dendrimers and guest molecules.