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

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. 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. 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.

蛋白激酶是细胞功能的关键调节因子，在许多人类疾病的发生和发展中起着至关重要的作用。许多激酶抑制剂已被用于这些疾病（如癌症和炎症）的分子靶向治疗。然而，这些高度疏水的激酶抑制剂具有生物利用度差和体内半衰期有限的共同特点，这严重阻碍了它们的实际应用。我们之前的研究表明，微生物合成的可生物降解聚酯聚（3 - 羟基丁酸酯 - 共 - 3 - 羟基己酸酯）（PHBHHx），聚羟基脂肪酸酯（PHA）家族的一员，可以作为这些疏水激酶抑制剂的一种有前景的递送纳米载体。最近，一种新型天然合成的杂化共聚物，聚乙二醇200封端的PHBHHx（PHBHHxPEG）通过嗜水气单胞菌发酵产生。在这项研究中，制备了新型的PHBHHxPEG纳米粒子，并对其作为细胞内递送纳米载体用于疏水激酶抑制剂的缓释进行了研究。 通过乳化 - 溶剂蒸发法制备的PHBHHxPEG纳米粒子（NPs）呈球形，直径约为200纳米。雷帕霉素在PHBHHxPEG纳米粒子中的包封率为91.9%，并且雷帕霉素从PHBHHxPEG纳米粒子中可以实现近10天的缓释。PHBHHxPEG纳米粒子的细胞摄取量明显高于PHBHHx纳米粒子。载雷帕霉素的PHBHHxPEG纳米粒子的抗增殖作用和mTOR抑制能力强于载药的PHBHHx纳米粒子和游离的雷帕霉素。 PHBHHxPEG纳米粒子能够实现雷帕霉素的高效包封和缓释。这种新型的可生物降解的PHBHHxPEG似乎是一种有前景的纳米载体，可用于疏水激酶抑制剂的持续递送，具有改善的细胞摄取和激酶抑制效率。