Department of Industrial and Physical Pharmacy, Purdue University, 575 West Stadium Avenue, West Lafayette, IN 47907, USA; Department of Pharmaceutics, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt.
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.
J Control Release. 2022 Dec;352:637-651. doi: 10.1016/j.jconrel.2022.10.041. Epub 2022 Nov 5.
Carfilzomib (CFZ) is a second-generation proteasome inhibitor effective in blood cancer therapy. However, CFZ has shown limited efficacy in solid tumor therapy due to the short half-life and poor tumor distribution. Albumin-coated nanocrystal (NC) formulation was shown to improve the circulation stability of CFZ, but its antitumor efficacy remained suboptimal. We hypothesize that NC size reduction is critical to the formulation safety and efficacy as the small size would decrease the distribution in the reticuloendothelial system (RES) and selectively increase the uptake by tumor cells. We controlled the size of CFZ-NCs by varying the production parameters in the crystallization-in-medium method and compared the size-reduced CFZ-NCs (z-average of 168 nm, NC) with a larger counterpart (z-average of 325 nm, NC) as well as the commercial CFZ formulation (CFZ-CD). Both CFZ-NCs showed similar or higher cytotoxicity than CFZ-CD against breast cancer cells. NC showed greater uptake by cancer cells, less uptake by macrophages and lower immune cell toxicity than NC or CFZ-CD. NC, but not NC, showed a similar safety profile to CFZ-CD in vivo. The biodistribution and antitumor efficacy of CFZ-NCs in mice were also size-dependent. NC showed greater antitumor efficacy and tumor accumulation but lower RES accumulation than NC in 4T1 breast cancer model. These results support that NC formulation with an optimal particle size can improve the therapeutic efficacy of CFZ in solid tumors.
卡非佐米（CFZ）是一种有效的第二代蛋白酶体抑制剂，用于血液癌症的治疗。然而，由于半衰期短和肿瘤分布不佳，CFZ 在实体瘤治疗中的疗效有限。白蛋白包覆纳米晶体（NC）制剂显示出改善 CFZ 循环稳定性的作用，但抗肿瘤疗效仍不理想。我们假设 NC 的尺寸减小对于制剂的安全性和疗效至关重要，因为较小的尺寸会减少在网状内皮系统（RES）中的分布，并选择性地增加肿瘤细胞的摄取。我们通过在介质中结晶法改变生产参数来控制 CFZ-NC 的尺寸，并将减小尺寸的 CFZ-NC（平均粒径为 168nm，NC）与较大的 CFZ-NC（平均粒径为 325nm，NC）以及商业 CFZ 制剂（CFZ-CD）进行比较。两种 CFZ-NC 对乳腺癌细胞的细胞毒性均与 CFZ-CD 相似或更高。NC 对癌细胞的摄取量大于巨噬细胞，对免疫细胞的毒性小于 NC 或 CFZ-CD。NC 而不是 NC，在体内与 CFZ-CD 具有相似的安全性。CFZ-NC 在小鼠中的分布和抗肿瘤疗效也与尺寸有关。NC 在 4T1 乳腺癌模型中比 NC 具有更大的抗肿瘤疗效和肿瘤积累，但 RES 积累较低。这些结果支持具有最佳粒径的 NC 制剂可以提高 CFZ 在实体瘤中的治疗效果。
