Bhattacharyya Jayanta, Bellucci Joseph J, Weitzhandler Isaac, McDaniel Jonathan R, Spasojevic Ivan, Li Xinghai, Lin Chao-Chieh, Chi Jen-Tsan Ashley, Chilkoti Ashutosh
Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708-0281, USA.
1] Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708-0281, USA [2] Department of Chemical Engineering, Institute for Molecular and Cellular Biology, University of Texas at Austin, Austin, Texas 78712-1062, USA.
Nat Commun. 2015 Aug 4;6:7939. doi: 10.1038/ncomms8939.
Packaging clinically relevant hydrophobic drugs into a self-assembled nanoparticle can improve their aqueous solubility, plasma half-life, tumour-specific uptake and therapeutic potential. To this end, here we conjugated paclitaxel (PTX) to recombinant chimeric polypeptides (CPs) that spontaneously self-assemble into ∼60 nm near-monodisperse nanoparticles that increased the systemic exposure of PTX by sevenfold compared with free drug and twofold compared with the Food and Drug Administration-approved taxane nanoformulation (Abraxane). The tumour uptake of the CP-PTX nanoparticle was fivefold greater than free drug and twofold greater than Abraxane. In a murine cancer model of human triple-negative breast cancer and prostate cancer, CP-PTX induced near-complete tumour regression after a single dose in both tumour models, whereas at the same dose, no mice treated with Abraxane survived for >80 days (breast) and 60 days (prostate), respectively. These results show that a molecularly engineered nanoparticle with precisely engineered design features outperforms Abraxane, the current gold standard for PTX delivery.
将具有临床相关性的疏水性药物包装到自组装纳米颗粒中，可以提高其水溶性、血浆半衰期、肿瘤特异性摄取和治疗潜力。为此，我们将紫杉醇（PTX）与重组嵌合多肽（CPs）偶联，这些多肽能自发自组装成约60纳米的近单分散纳米颗粒，与游离药物相比，PTX的全身暴露量增加了7倍，与美国食品药品监督管理局批准的紫杉烷纳米制剂（Abraxane）相比增加了2倍。CP-PTX纳米颗粒的肿瘤摄取量比游离药物高5倍，比Abraxane高2倍。在人三阴性乳腺癌和前列腺癌的小鼠癌症模型中，CP-PTX在两种肿瘤模型中单次给药后均诱导了近乎完全的肿瘤消退，而在相同剂量下，接受Abraxane治疗的小鼠分别没有存活超过80天（乳腺癌）和60天（前列腺癌）。这些结果表明，具有精确工程设计特征的分子工程纳米颗粒优于目前PTX递送的金标准Abraxane。
