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1、钟伟童药用高分子材料学09301030044An 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 con
2、siderable attention both in the field of drug & gene delivery application and biological response modification. In this article, I will explore several latest application of Pluronic in the field of pharmaceutics.Key words:Pluronic; nanomedcine; gene delivery; Multidrug resistance; drug delivery sys
3、temIntroduction:Polymer nanomaterial like Pluronic has sparked a considerable interest as vehicles used for diagnostic and therapeutic agents; research in nanomedicine has not only become a frontier movement but is also a revolutionizing drug delivery field. A common approach for building a drug del
4、ivery system is to incorporate the drug within the nanocarrier that results in increased solubility, metabolic stability, and improved circulation time1 Pluronic block copolymers: Evolution of drug delivery concept from inertnanocarriers to biological response modifiers, Elena V. Batrakova , Alexand
5、er V. Kabanov, Journal of Controlled Release, 981062 Paclitaxel-loaded Pluronic nanoparticles formed by a temperature-induced phase transition for cancer therapy. Keun Sang Oh, Ji Yung Song, Sun Hang Cho, etc., Journal of Controlled Release 148 (2010) 344350. In the meantime, nanoparticle with steal
6、th 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 resistan
7、ce 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 significant
8、 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 micelles showed tha
9、t 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-killing eff
10、ect 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-glycoprotein, Pgp
11、. 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 Pgp drug efflux pump, which involves interaction of Pluronic molecules with MDR cell membranes, de
12、crease 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 source3 E.V. Batrakova, S. Li, W.F. Elmquist, D.W. Miller, V.Y. Alakhov, A.V. Kabanov,
13、 Mechanism of sensitization of MDR cancer cells by Pluronic block copolymers: selective energy depletion, Br. J. Cancer 85 (12) (2001) 19871997.4 T. Minko, E.V. Batrakova, S. Li, Y. Li, R.I. Pakunlu, V.Y. Alakhov, A.V. Kabanov, Pluronic block copolymers alter apoptotic signal transduction of doxorub
14、icin in drug-resistant cancer cells, J. Control. Release 105 (3) (2005) 269278.5 A. Venne, S. Li, R. Mandeville, A. Kabanov, V. Alakhov, Hypersensitizing effect of Pluronic L61 on cytotoxic activity, transport, and subcellular distribution of doxorubicin in multiple drug-resistant cells, Cancer Res.
15、 56 (1996) 36263629.6 Drug delivery in Pluronic micelles: effect of high-frequency ultrasound on drug release from micelles and intracellular uptake, Alexandre Marin , Hao Sun , Ghaleb A. Husseini , William G. Pitt , Douglas A. Christensen, Natalya Y. Rapoport, Journal of Controlled Release 84 (2002
16、) 39477 Delivery of a lentiviral vector in a Pluronic F127 gel to cells of the central nervous system, Padraig M. Strappe, David W. Hampton, Begona Cachon-Gonzalez, James W. Fawcett, Andrew Lever, European Journal of Pharmaceutics and Biopharmaceutics 61 (2005) 1261338 Pluronic block copolymers alte
17、r apoptotic signal transduction of doxorubicin in drug-resistant cancer cells, Tamara Minko, Elena V. Batrakovab, Shu Lib, Yili Lib, Refika I. Pakunlua,Valery Yu. Alakhov, Alexander V. Kabanov, Journal of Controlled Release 105 (2005) 2692789 Adipose differentiation of bone marrow-derived mesenchyma
18、l stem cells using Pluronic F-127 hydrogelin vitro Vashi, Aditya V. Keramidaris, Efthimia , Abberton, Keren M. Biomaterials Volume 29, Issue 5, February 2008, Pages 573-57910 Regional delivery of vancomycin using Pluronic F-127 to inhibit methicillin resistant Staphylococcus aureus (MRSA) growth in
19、chronic otitis media in vitro and in vivo, Sang Heun Lee, Ji Eun Lee, Woon Yi Baek, Jeong Ok Lim, Journal of Controlled Release 96 (2004) 1 711 Sustained Ocular Drug Delivery from a Temperature and pH Triggered Novel In Situ Gel System, Himanshu Gupta, Sanyog Jain, Rashi Mathur, etc., Drug Delivery,
20、 14:507515, 200712 Differential metabolic responses to Pluronic in MDR and non-MDR cells: A novel pathway for chemosensitization of drug resistant cancers, Daria Yu. Alakhova , Nataliya Y. Rapoport, Elena V. Batrakova , etc., Journal of Controlled Release 142 (2010) 8910013 Difunctional Pluronic cop
21、olymer micelles for paclitaxel delivery: Synergistic effect of folate-mediated targeting and Pluronic-mediated overcoming multidrug resistance in tumor cell lines Yongzhong Wang, Li Yuc, Limei Han, Xianyi Sha, Xiaoling Fang, International Journal of Pharmaceutics 337 (2007) 637314 DNA nanogels compo
22、sed of chitosan and Pluronic with thermo-sensitive and photo-crosslinking properties, Jung Im Lee, Hye Sung Kim, Hyuk Sang Yoo, International Journal of Pharmaceutics 373 (2009) 939915 Lipid composition determines interaction of liposome membranes with Pluronic L61, Artem E. Zhirnov , Tatiana V. Dem
23、ina , Oxana O. Krylova, etc., Biochimica et Biophysica Acta 1720 (2005) 73 83. Third, they promote generation of reactive oxygen species (ROS) and simultaneously inhibit the glutathione/glutathione S-transferase (GSH/GST) detoxification by decreasing GSH and inhibiting GST activity. Fourth, they att
24、enuate drug sequestration in acidic vesicles, which may increase drug bioavailability within the cancer cell . Finally, they decrease membrane potential in mitochondria of MDR cells, promote release of cytochrome C and overall enhance proapoptotic signaling and mitigate anti-apoptotic cellular defen
25、se of MDR cells. It is also remarkable that despite rather simple structure and lack of precise spatial arrangement of 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
26、level of Pgp expression in the cancer cells.1.3 Assisted drug release.In addition, a new modality of drug targeting to 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
27、approach is that drug encapsulation in micelles decreases systemic concentration of drug, diminishes intracellular drug 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
28、circulatory system. Due to passive targeting, micelle-encapsulated drugs accumulate at the interstitial space in the 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. A
29、n 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 drug encapsulation in polymeric
30、micelles followed by tumor sonication by focused high-frequency ultrasound beam.2, Application of Pluronics hydrogels in gene deliveryPluronic F 127(PF127) in aqueous solution at concentrations of 1520% and higher exhibits the unique property of reversible thermal gelation. When the temperature of a
31、n aqueous solution of F127 is increased, the co-polymer molecules aggregate into spherical micelles, which contain a dehydrated polyoxypropylene (PPO) core and an outer shell of hydrated Polyoxyethylene (PEO) chains. This unique property of being liquid at 4 8C and in a semi solid gel at room or bod
32、y temperature provides an attractive platform for slow release of drugs. 2.1 Delivery of lentiviral vectorsPoloxamer based gels have previously been used to deliver adenoviral vectors to cells of the vasculature both in vitro and in vivo. the data indicates that Pluronic F127 gel can successfully co
33、ntain a lentiviral vectors and allow delivery to cells in vitro without causing damage or loss of titre to the vector or toxicity to primary glial cultures. Stereotaxic delivery of vector and gel to the brain is possible but is associated with tissue damage and inflammation.2.2 Delivery of other non
34、-viral gene carriersGene therapy employing non-viral carriers has received much attention because of such carriers superior safety in comparison with viral counterparts. While colloidal gene carriers have been widely employed for the purpose of systemic circulation, local treatments of gene carriers
35、 have been relatively less investigated due to lack of proper delivery systems. Several research projects have been done to develop efficient delivery carriers with the aim of localizing gene expression around injection sites. Among those, hydrogels were employed for this purpose because of their su
36、perior injectability and biocompatibility. Hydrogels composed of triblock copolymers were most often employed to prepare thermo-sensitive hydrogels for controlled release of plasmid DNA.Photo-crosslinkable hydrogels composed of chitosan and Pluronic were fabricated for enhanced local delivery of tra
37、nsgenes. Complex formation of released DNA and released medium was observed by agarose gel electrophoresis and scanning electron microscopy. Enhanced transfection efficiencieswere observed when released fractions from chitosan/Pluronic hydrogels were employed for in vitro studies.3, Application of P
38、luronics hydrogels in other in situ drug delivery3.1 In stem cell deliveryDue to increasing clinical demand for adipose tissue, a suitable scaffold for engineering adipose tissue constructs is needed. In recent study, scientists have developed a three-dimensional (3-D) culture system using bone marr
39、ow-derived mesenchymalstem cells(BM-MSC) and aPluronicF-127 hydrogel scaffold as a step towards thein vitrotissue engineering of fat. BM-MSC were dispersed into aPluronicF-127 hydrogel with or without type I collagen added. The adipogenic differentiation of the BM-MSC was assessed by cellular morpho
40、logy and further confirmed by Oil Red O staining. The BM-MSC differentiated into adipocytes inPluronicF-127 in the presence of adipogenic stimuli over a period of 2 weeks, with some differentiation present even in absence of such stimuli. The addition of type I collagen to thePluronicF-127 caused th
41、e BM-MSC to aggregate into clumps, thereby generating an uneven adipogenic response, which was not desirable.Scientists have developed a 3-Din vitromodel for adipose tissue engineering based on BM-MSC andPluronicF-127 hydrogel.PluronicF-127 has provided a suitable 3-D environment for differentiation
42、 of BM-MSC into adipocytes, providing a potential alternativecellsource for adipose tissue engineering.3.2 In Ocular Drug DeliveryVarious ocular diseases like glaucoma, conjunctivitis, and dry eye syndrome require frequent drug administration. Poor ocular bioavailability of drugs (1%) from conventio
43、nal eye drops is due mainly to the precorneal loss factors that include rapid tear turnover, nonproductive absorption, transient residence time in the cul-de-sac, and the relative impermeability of the drugs to corneal epithelial membrane. These problems may be overcome by the use of in situ gel-for
44、ming systems that are instilled as drops into the eye and undergo a sol-gel transition in the cul-de-sac.The latest work describes the formulation and evaluation of an ocular delivery system based on the concept of both temperature and pH-triggered in situ gelation. Pluronic F-127 (a thermosensitive
45、 polymer) in combination with chitosan (pH sensitive polymer also acts as permeation enhancer) was used as gelling agent. The work showed that the developed chitosan/Pluronic F-127 based ophthalmic formulation of timolol maleate was nonirritant, enhanced transcorneal drug permeation, and prolonged t
46、he retention at corneal site. It is suitable for sustained topical drug delivery to eyes for rational drug therapy for glaucoma and other eye related disorders and can go up to the clinical level.3.3 In antibiotics deliveryThe prevention and treatment of deep-seated infections in very poorly vascula
47、rized sites, such as bones and prosthetic devices, remain difficult with conventional systemic antibiotic therapy. Therefore, a new system using a drug delivery system is needed for local antibiotic therapy. The ideal matrix for local antibiotic delivery should meet the following criteria: sufficien
48、t drug carriage, good tolerability, biodegradability, controlled release, and no toxicity when placed at a mobile site. Pluronic F-127 gel fulfills all the above conditions, consisting by weight of approximately 70% ethylene oxide and 30% propylene oxide. The material dissolves slowly, is cleared by
49、 renal and biliary excretion, is soluble in water, and becomes a hydrogel at room temperature in concentrations above 20% .Vancomycin is a potent therapeutic agent being used for treating methicillin resistant Staphylococcus aureus (MRSA), however it induces systemic toxicity by repeated usage and patients with MRSA should be admitted to hospital to take regular oral intake and intravenous injection of vancomycin. Conclusively proof was foun