Microbial synthesized biodegradable PHBHHxPEG hybrid copolymer as an efficient intracellular delivery nanocarrier for kinase inhibitor.
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.
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. luxy05@mail.xjtu.edu.cn.
Xiao-Yun
XY
Lu
Ming-Chuan
MC
Li
Xin-Liang
XL
Zhu
Fan
F
Fan
Lei-Lei
LL
Wang
Jian-Gang
JG
Ma
D020155:3-Hydroxybutyric Acid / Q000096:biosynthesis* / Q000737:chemistry; D016980:Aeromonas hydrophila / Q000378:metabolism; D000818:Animals; D002208:Caproates / Q000737:chemistry; D045744:Cell Line, Tumor; D003692:Delayed-Action Preparations / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry*; D004705:Endocytosis; D005285:Fermentation; D006801:Humans; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D020123:Sirolimus / Q000737:chemistry; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000094122:Polyhydroxybutyrates
D020155:3-Hydroxybutyric Acid; D002208:Caproates; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D047428:Protein Kinase Inhibitors; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C115940:poly(3-hydroxybutyrate-co-3-hydroxyhexanoate); D000094122:Polyhydroxybutyrates; C546842:MTOR protein, human