Abstract
For anticancer drug delivery systems, many systems have been discussed and exemplified regarding as traditional systems such as polymer-based therapeutics, liposomes, and inorganic particles. Polymer therapeutic is considered to be a potential candidate displaying well bioavailability and high molecular manipulation for use in cancer treatment. The term polymer therapeutics describes several distinct classes of agent, including polymer-drug conjugates, micelles and mixed micelles that have now entered clinical development because of their intrinsic physical properties and their abilities to target specific locations. Much research has recently been focused on the study of mixed micelles as drug carriers in the hunt for improved cancer therapy. The potential advantages of mixed micelles as potential drug carriers include 1) the fact that they can be degraded into nontoxic substances that may be readily excreted by the body; 2) the possibility of modulating the micellar structure to improve intracellular drug delivery; and 3) the possibility of modifying the polymers for in vivo cancer targeting and imaging. Despite such potential advantages, in vivo studies on mixed micelles as potential anticancer drug delivery systems remain scanty. The major problem that limits the wider application of mixed micelles as a drug carrier is the uncertainty about the structure of micelles during micellization in individual and mixed micellar systems. Therefore, my major is focus on the mixed micellar systems for the in vivo application, as follows: (1) The Accumulation of Dual pH and Temperature Responsive Micelles in Tumors An optimized, biodegradable, dual temperature- and pH- responsive micelle system prepared from methoxy poly(ethylene glycol)-block-poly(N- (2-hydroxypropyl) methacrylamide dilactate)-co-(N-(2-hydroxypropyl) methacrylamide-co-histidine) (mPEG-b-P(HPMA-Lac-co-His)) copolymer and methoxy poly(ethylene glycol)-block-poly(D,L-lactide) (mPEG-b-PLA) copolymer conjugated with functional group Cy 5.5 was prepared in order to enhance tumor accumulation. Anticancer drug, doxorubicin was incorporated into the inner core of micelle by hot shock protocol. The size and stability of the micelle were controlled by the copolymer composition and is fine tuned to extracellular pH of tumor. The mechanism then caused pH change and at body temperature which induce doxorubicin release from micelles and have strong effects on the viability of HeLa, ZR-75-1, MCF-7 and H661 cancer cells. Our in vivo results revealed a clear distribution of Doxorubicin-loaded mixed micelle (Dox-micelle) and efficiency targeting tumor site with particles increasing size in the tumor interstitial space, and the particles could not diffuse throughout the tumor matrix. In vivo tumor growth inhibition showed that Dox-micelle exhibited excellent antitumor activity and a high rate of anticancer drug in cancer cells by this strategy. (2) Rapamycin Encapsulated in Dual-Responsive Micelles for Intracellular Drug Delivery Rapamycin has been developed as a potential anticancer drug for treatment in rapamycin-sensitive cancer models, but its poor water solubility greatly hampers the application to cancer therapy. This study investigated the preparation, release profiles, uptake and in vitro/in vivo study of a dual responsive micellar formulation of rapamycin. Rapamycin-loaded micelles (rapa-micelles) measured approximately ca. 150 nm with narrow size distribution and high stability in bovine serum albumin solution. It was shown that rapamycin could be loaded efficiently in mixed micelles up to a concentration of 1.8 mg/mL by a hot shock protocol. Rapamycin release kinetic studies demonstrated that this type of micellar system could be applied in physiological conditions under varied pH environments. Confocal and pH-topography imaging revealed a clear distribution of rapa-micelles, and visible intracellular pH changes which induced encapsulated rapamycin to be released and then induced autophagolysosome formation. In vivo tumor growth inhibition showed that rapa-micelles exhibited excellent antitumor activity and a high rate of apoptosis in HCT116 cancer cells. These results indicated that dual responsive mixed micelles provided a suitable delivery system for the parenteral administration of drugs with poor water solubility, such as rapamycin, in cancer therapy. (3) Graft and Diblock Micelles with Enhanced Stability for Overcoming Multidrug Resistance in Cancer A graft and diblock polymeric micelles, self-assembling from poly(N-(2-hydroxypropyl) methacrylamide dilactate)-co-(N-(2-hydroxypropyl) methacrylamide-co-histidine)-graft-poly(D,L-lactide) graft copolymers and methoxyl/functionalized-PEG-b-PLA diblock copolymers, as an anticancer drug doxorubicin carrier for cancer targeting, imaging, and overcoming multidrug resistance in cancer therapy. This high stability nanoparticle exhibited a pH-dependent drug release behavior, owning to the pH-sensitive structure of imidazole of histidine, to release doxorubicin in acidic surroundings (intracellular endosomes) and to capsulate doxorubicin in neutral surroundings (blood circulation or extracellular matrix). The in vitro results revealed released doxorubicin from mixed micelles was more effective accumulation into the nuclei than free doxorubicin. Imaging by in vivo image system showed that high stability ensures a high intratumoral accumulation due to EPR effect. Mixed micelles with enhanced stability inherently overcome a certain degree of multidrug resistance by tumor cells, since such vesicles can deliver between more drug to solid lesions when compared with the administered drug in its free drug. In vivo tumor growth inhibition shows that nanoparticles exhibited excellent antitumor activity and a high rate of apoptosis in cancer cells. The results indicate that the high stbility carriers with a pH-dependent drug release can be allowed to accurately deliver to targeted tumors for multidrug-resistant cancer therapy.