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1、钟伟童药用高分子材料学093010300441An overview of the application of Pluronic in the field of pharmaceutics钟伟童 09301030044 (复旦大学药学院)Abstract:Pluronic, amphiphilic block copolymers of poly (ethylene oxide) and poly (propylene oxide), are commercially available pharmaceutical excipients. They recently attracted c
2、onsiderable attention both in the field of drug nanomedcine; gene delivery; Multidrug resistance; drug delivery systemIntroduction:Polymer nanomaterial like Pluronic has sparked a considerable interest as vehicles used for diagnostic and therapeutic agents; research in nanomedicine has not only beco
3、me a frontier movement but is also a revolutionizing drug delivery field. A common approach for building a drug delivery system is to incorporate the drug within the nanocarrier that results in increased solubility, metabolic stability, and improved circulation timei. In the meantime, nanoparticle w
4、ith stealth property can hide themselves from reticuloendothelial system (RES) and other immune system is one of the most promising area of nanomedcine. However, recent study shows that Pluronic can also modify certain biological reactions in cells, which could be a new approach to reverse multidrug
5、 resistance that occurs in several type of cancers. In the meantime, In situ forming polysaccharide-based 3D-hydrogels are often used for ocular drug delivery, DNA delivery and cell delivery in regenerative medicine. Since Pluronic is a very promising material in the field of nanomedcine, it is of s
6、ignificant importance to explore its latest application in pharmaceutics not only to review the achievement but also directing the further research.1、self-assembly micelles and labeled micelles formed by Pluronic copolymers. 1.1 Reversing MDR effect. Recent studies on paclitaxel (PTX) loaded micelle
7、s showed that Pluronic micellar PTX significantly reduced IC50 of PTXin MDR cells compared to free PTX, and MDR cells are more susceptible to the cytotoxic effects of Pluronic micellar PTX than the parental cells. The introduction of folic acid into P105 or P105/L101 mixed micelles enhanced the cell
8、-killing effect by active internalization. Increased internalization explained the improved cytotoxicity of the FOL-micellar PTX to tumor cells. Another study showed the interactions between Pluronic micelles and P-glycoprotein(Pgp) that may partly explain the result ablve. 1.2 Inhibiting the P-glyc
9、oprotein, Pgp. Contrary to most low molecular mass inhibitors of Pgp, that are tailored to interact specifically with the transport system protein, Pluronics have a broad spectrum of activities. First, they inhibit 钟伟童药用高分子材料学093010300442Pgp drug efflux pump, which involves interaction of Pluronic m
10、olecules with MDR cell membranes, decrease in membrane microviscosity and inhibition of Pgp ATPase activity. Second, they inhibit respiratory chain complexes in mitochondria of MDR cells and thus deplete ATP that deprives the MDR cells of the energy sourceii. Third, they promote generation of reacti
11、ve oxygen species (ROS) and simultaneously inhibit the glutathione/glutathione S-transferase (GSH/GST) detoxification by decreasing GSH and inhibiting GST activity. Fourth, they attenuate drug sequestration in acidic vesicles, which may increase drug bioavailability within the cancer cell . Finally,
12、 they decrease membrane potential in mitochondria of MDR cells, promote release of cytochrome C and overall enhance proapoptotic signaling and mitigate anti-apoptotic cellular defense of MDR cells. It is also remarkable that despite rather simple structure and lack of precise spatial arrangement of
13、pharmacophoric groups, Pluronics appear to be selective with respect to the MDR cell phenotype. This is most noticeably seen in ATP depletion by Pluronic, which correlates with the level of Pgp expression in the cancer cells. 1.3 Assisted drug release. In addition, a new modality of drug targeting t
14、o tumors currently developed is based on the drug in polymeric micelles followed by the localized release at the tumor site triggered by focused ultrasound. The rationale behind this approach is that drug encapsulation in micelles decreases systemic concentration of drug, diminishes intracellular dr
15、ug uptake by normal cells, and provides for a passive drug targeting to tumors; the micelles should be stable enough to withstand dilution associated with the administration into the circulatory system. Due to passive targeting, micelle- encapsulated drugs accumulate at the interstitial space in the
16、 tumor; however, the intracellular uptake of the micelle-encapsulated drug is much lower than that of a free drug. To enhance the intracellular uptake, we use ultrasonic irradiation. An important advantage of ultrasound is that it is noninvasive, can penetrate deep into the interior of the body, can be focused and carefully controlled. High frequency ultrasound may be instrumental in developing a new technique of drug targeting to tumors, based on d
