Kumar Dulla Naveen, Chaudhuri Aiswarya, Dehari Deepa, Shekher Anusmita, Gupta Subash C, Majumdar Shreyasi, Krishnamurthy Sairam, Singh Sanjay, Kumar Dinesh, Agrawal Ashish Kumar
Department of Pharmaceutical Engineering and Technology, Indian Institute of Technology (Banaras Hindu University), Varanasi 221005, India.
Department of Biochemistry, Institute of Science, Banaras Hindu University, Varanasi 221005, India.
Life (Basel). 2022 Jul 28;12(8):1143. doi: 10.3390/life12081143.
Paclitaxel (PAC) has been approved by FDA for clinical use (Taxol), yet dose-dependent severe toxicity due to the adjuvant Cremophor EL in combination with ethanol is a major drawback. The drawbacks of the current therapy can be overcome by (i) finding a suitable vehicle that cannot only bypass the above adjuvant but also be used to deliver drugs orally and (ii) combining the PAC with some other chemotherapeutics to have the enhanced therapeutic efficacy. In the current work, we have used folic acid (FA) functionalized bovine milk-derived exosomes for oral delivery of PAC in combination with 5-fluorouracil (5-FU). Exosomes before and after the drug loading were found to have a particle size in the range of 80-100 nm, polydispersity index (PDI 0.20), zeta potential (-25 mV), entrapment efficiency (82%), practical drug loading (28%) and sustained drug release for 48 h. Significant decreases in IC were observed in the case of exosomes loaded drugs which further improved following the FA functionalization. FA functionalized coumarin-6-loaded exosomes showed remarkably higher cellular uptake in comparison with free coumarin-6. Moreover, FA-functionalized drug-loaded exosomes showed a higher apoptotic index with better control over cell migration. Collectively, data suggested the enhanced efficacy of the combination following its loading to the folic acid functionalized exosomes against breast cancer.
紫杉醇（PAC）已被美国食品药品监督管理局（FDA）批准用于临床（商品名泰素），然而，由于辅助剂聚氧乙烯蓖麻油（Cremophor EL）与乙醇联用会产生剂量依赖性的严重毒性，这是一个主要缺点。当前治疗方法的缺点可以通过以下方式克服：（i）找到一种合适的载体，它不仅可以绕过上述辅助剂，还可用于口服给药；（ii）将PAC与其他一些化疗药物联合使用，以提高治疗效果。在当前的研究中，我们使用了叶酸（FA）功能化的牛乳源外泌体来口服递送PAC，并联合5-氟尿嘧啶（5-FU）。发现载药前后的外泌体粒径在80-100nm范围内，多分散指数（PDI约为0.20），zeta电位（约-25mV），包封率（约82%），实际载药量（约28%），且药物可持续释放48小时。载药外泌体的半数抑制浓度（IC）显著降低，在进行FA功能化后进一步改善。与游离香豆素-6相比，FA功能化的载香豆素-6外泌体显示出明显更高的细胞摄取。此外，FA功能化的载药外泌体显示出更高的凋亡指数，并能更好地控制细胞迁移。总体而言，数据表明，将药物负载到叶酸功能化外泌体中后，联合用药对乳腺癌的疗效增强。
