Microbial synthesized biodegradable PHBHHxPEG hybrid copolymer as an efficient intracellular delivery nanocarrier for kinase inhibitor

BMC Biotechnology

Xiao-Yun Lu²  Ming-Chuan Li¹  Xin-Liang Zhu²  Fan Fan²  Lei-Lei Wang²  Jian-Gang Ma² 

[1] Molecular Biotechnology Center, Universita di Torino, 10126 Torino, Italy

[2] Department of Biological Science and Bioengineering, Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi’an Jiaotong University, Xi’an 710049, Shaanxi, P. R China

关键词: Drug delivery;    Nanoparticle;    Rapamycin;    PEG;    Polyhydroxyalkanoate;   

Others  :  1230602
DOI  :  10.1186/1472-6750-14-4

 received in 2013-08-15, accepted in 2014-01-11,  发布年份 2014

【 摘 要 】

Background

Protein Kinases are key regulators of cell function and play essential roles in the occurrence and development of many human diseases. Many kinase inhibitors have been used for molecular targeted treatment of those diseases such as cancer and inflammation. However, those highly hydrophobic kinase inhibitors shared the common features of poor bioavailability and limited in vivo half-life, which strongly impeded their practical applications. Our previous study demonstrated that microbial synthesized biodegradable polyester poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx), a member of polyhydroxyalkanoates (PHAs) family, could serve as a promising delivery nanocarrier for those hydrophobic kinase inhibitors. Recently, a novel natural synthesized hybrid copolymer, PEG200 end-capped PHBHHx (PHBHHxPEG) was produced by Aeromonas hydrophila fermentation. In this study, the novel PHBHHxPEG NPs were prepared and investigated to serve as intracellular delivery nanocarriers for sustained release of hydrophobic kinase inhibitors.

Results

PHBHHxPEG nanoparticles (NPs) prepared by an emulsification–solvent evaporation method were spherical with a diameter around 200 nm. The entrapment efficiency on rapamycin in PHBHHxPEG NPs was 91.9% and the sustained release of rapamycin from PHBHHxPEG NPs could be achieved for almost 10 days. The cellular uptake of PHBHHxPEG NPs was significant higher than that of PHBHHx NPs. The anti-proliferation effect and mTOR inhibition ability of rapamycin-loaded PHBHHxPEG NPs was stronger than that of drug-loaded PHBHHx NPs and free rapamycin.

Conclusions

PHBHHxPEG NPs could achieve the efficient entrapment and sustained release of rapamycin. The novel biodegradable PHBHHxPEG appeared a promising nanocarrier for sustained delivery of hydrophobic kinase inhibitors with improved cellular uptake and kinase inhibition efficiency.

【 授权许可】

   
2014 Lu et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Kahan BD, Camardo JS: Rapamycin: clinical results and future opportunities. Transplantation 2001, 72(7):1181-1193.
• [2]Meric-Bernstam F, Gonzalez-Angulo AM: Targeting the mTOR Signaling Network for Cancer Therapy. J Clin Oncol 2009, 27(13):2278-2287.
• [3]Douros J, Suffness M: New Anti-Tumor Substances Of Natural Origin. Cancer Treat Rev 1981, 8(1):63-87.
• [4]Simamora P, Alvarez JM, Yalkowsky SH: Solubilization of rapamycin. Int J Pharm 2001, 213(1–2):25-29.
• [5]Dias VC, Yatscoff RW: An in vitro method for predicting in vivo oral bioavailability of novel immunosuppressive drugs. Clin Biochem 1996, 29(1):43-49.
• [6]Chen GQ, Wu Q: The application of polyhydroxyalkanoates as tissue engineering materials. Biomaterials 2005, 26(33):6565-6578.
• [7]Wu Q, Wang Y, Chen GQ: Medical application of microbial biopolyesters polyhydroxyalkanoates. Artif Cells Blood Substit Biotechnol 2009, 37(1):1-12.
• [8]Lu XY, Ciraolo E, Stefenia R, Chen GQ, Zhang YL, Hirsch E: Sustained release of PI3K inhibitor from PHA nanoparticles and in vitro growth inhibition of cancer cell lines. Appl Microbiol Biotechnol 2011, 89(5):1423-1433.
• [9]Xiong YC, Yao YC, Zhan XY, Chen GQ: Application of polyhydroxyalkanoates nanoparticles as intracellular sustained drug-release vectors. J Biomater Sci-Polym Ed 2010, 21(1):127-140.
• [10]Zhang YL, Lu XY, Liu QQ, Li MC, Yang ZQ, Ma JG: Production and characterization of poly(3-hydroxybutyrate-co-3-hydroxyhexanoate)-poly(ethylene glycol) hybird copolymer with adjustable molecular weight. Chin J Polymer Sci 2012, 30(1):101-111.
• [11]Blaser B, Waselle L, Dormond-Meuwly A, Dufour M, Roulin D, Demartines N, Dormond O: Antitumor activities of ATP-competitive inhibitors of mTOR in colon cancer cells. BMC Cancer 2012, 12:86.
• [12]Foster DA, Toschi A: Targeting mTOR with rapamycin: one dose does not fit all. Cell Cycle 2009, 8(7):1026-1029.
• [13]Shi JJ, Votruba AR, Farokhzad OC, Langer R: Nanotechnology in Drug Delivery and Tissue Engineering: From Discovery to Applications. Nano Lett 2010, 10(9):3223-3230.
• [14]Langer R: Drug delivery and targeting. Nature 1998, 392(6679):5-10.
• [15]Mora-Huertas CE, Fessi H, Elaissari A: Polymer-based nanocapsules for drug delivery. Int J Pharm 2010, 385(1–2):113-142.
• [16]Wang M, Thanou M: Targeting nanoparticles to cancer. Pharmacol Res 2010, 62(2, Sp. Iss. SI):90-99.
• [17]Yao YC, Zhan XY, Zhang J, Zou XH, Wang ZH, Xiong YC, Chen J, Chen GQ: A specific drug targeting system based on polyhydroxyalkanoate granule binding protein PhaP fused with targeted cell ligands. Biomaterials 2008, 29(36):4823-4830.
• [18]Yang XS, Zhao K, Chen GQ: Effect of surface treatment on the biocompatibility of microbial polyhydroxyalkanoates. Biomaterials 2002, 23(5):1391-1397.
• [19]van Vlerken LE, Vyas TK, Amiji MM: Poly(ethylene glycol)-modified nanocarriers for tumor-targeted and intracellular delivery. Pharm Res 2007, 24(8):1405-1414.
• [20]Gref R, Minamitake Y, Peracchia MT, Trubetskoy V, Torchilin V, Langer R: Biodegradable Long-Circulating Polymeric Nanospheres. Science 1994, 263(5153):1600-1603.
• [21]Perez C, Sanchez A, Putnam D, Ting D, Langer R, Alonso MJ: Poly(lactic acid)-poly(ethylene glycol) nanoparticles as new carriers for the delivery of plasmid DNA. J Control Release 2001, 75(1–2):211-224.
• [22]Li Q, Wang Y, Feng NP, Fan ZZ, Sun J, Nan YL: Novel polymeric nanoparticles containing tanshinone IIA for the treatment of hepatoma. J Drug Target 2008, 16(10):725-732.