Sharma Ankita, Kaur Amanpreet, Jain Upendra Kumar, Chandra Ramesh, Madan Jitender
Department of Pharmaceutics, Chandigarh College of Pharmacy, Mohali, Panjab, India.
Dr. B.R Ambedkar Centre for Biomedical Research, University of Delhi, Delhi, India; Department of Chemistry, University of Delhi, Delhi, India.
Colloids Surf B Biointerfaces. 2017 Jul 1;155:200-208. doi: 10.1016/j.colsurfb.2017.04.020. Epub 2017 Apr 12.
5-Fluorouracil (5-FU) is a first-line chemotherapeutic drug in colorectal cancer. However, intravenous administration of 5-FU at the dose of 7-12mg/kg exhibits curbs like short half-life (20min) and toxic side-effects on bone marrow cells. Therefore, in present investigation, 5-FU was conjugated to poly (ethylene glycol) anchored recombinant human serum albumin nanoparticles (5-FU-rHSA-PEG-NPs) to improve the pharmacokinetic and therapeutic profiles.
The mean particle size of 5-FU-rHSA-NPs was measured to be 44.3±5.8-nm, significantly (P<0.05) lesser than 65.7±7.2-nm of 5-FU-rHSA-PEG-NPs. In addition, zeta-potential of 5-FU-rHSA-NPs was estimated to be -10.2±2.6-mV significantly (P<0.05) lower than -25.8±3.5-mV of 5-FU-rHSA-PEG-NPs. Moreover, both 5-FU-rHSA-NPs and 5-FU-rHSA-PEG-NPs were smooth, spherical and regular in shape. In-vitro drug release analysis indicated that 5-FU-rHSA-NPs and 5-FU-rHSA-PEG-NPs separately released 10.9% and 9.23% of 5-FU in PBS (pH∼7.4) with no significant difference (P>0.05) up to 48h. However, addition of 20% v/v serum to PBS (pH∼7.4) boosted the drug release. 5-FU-rHSA-NPs and 5-FU-rHSA-PEG-NPs released 78.26% and 48.9% of the 5-FU up to 48h in presence of PBS (pH∼7.4 and 20% serum) with significant difference (P<0.05). Furthermore, 5-FU-rHSA-PEG-NPs displayed the IC of 3.7-μM significantly (P<0.05) lower than 6.8-μM and 11.2-μM of 5-FU-rHSA-NPs and 5-FU solution, respectively. One compartmental pharmacokinetic elements indicated that 5-FU-rHSA-PEG-NPs demonstrated the half-life (t) of 5.33±0.15-h significantly (P<0.001) higher than 1.50±0.08-h and 0.30±0.09-h of 5-FU-rHSA-NPs and 5-FU solution, respectively.
5-FU-rHSA-PEG-NPs tendered improved cytotoxicity and pharmacokinetic profile. Hence, 5-FU-rHSA-PEG-NPs must be further tested under stringent milieu for translating in to a clinical product.
5-氟尿嘧啶（5-FU）是结直肠癌的一线化疗药物。然而，以7-12mg/kg的剂量静脉注射5-FU存在诸如半衰期短（20分钟）以及对骨髓细胞有毒副作用等局限。因此，在本研究中，将5-FU与聚乙二醇锚定的重组人血清白蛋白纳米粒（5-FU-rHSA-PEG-NPs）偶联，以改善其药代动力学和治疗特性。
测得5-FU-rHSA-NPs的平均粒径为44.3±5.8纳米，显著（P<0.05）小于5-FU-rHSA-PEG-NPs的65.7±7.2纳米。此外，5-FU-rHSA-NPs的ζ电位估计为-10.2±2.6毫伏，显著（P<0.05）低于5-FU-rHSA-PEG-NPs的-25.8±3.5毫伏。而且，5-FU-rHSA-NPs和5-FU-rHSA-PEG-NPs均表面光滑、呈球形且形状规则。体外药物释放分析表明，5-FU-rHSA-NPs和5-FU-rHSA-PEG-NPs在PBS（pH约7.4）中分别释放了10.9%和9.23%的5-FU，在48小时内无显著差异（P>0.05）。然而，向PBS（pH约7.4）中添加20%（v/v）血清可促进药物释放。在PBS（pH约7.4和20%血清）存在的情况下，5-FU-rHSA-NPs和5-FU-rHSA-PEG-NPs在48小时内分别释放了78.26%和48.9%的5-FU，存在显著差异（P<0.05）。此外，5-FU-rHSA-PEG-NPs的半数抑制浓度（IC）为3.7微摩尔，显著（P<0.05）低于5-FU-rHSA-NPs的6.8微摩尔和5-FU溶液的11.2微摩尔。单室药代动力学参数表明，5-FU-rHSA-PEG-NPs的半衰期（t）为5.33±0.15小时，显著（P<0.001）高于5-FU-rHSA-NPs的1.50±0.将5-FU-rHSA-PEG-NPs进一步在严格环境下进行测试，以转化为临床产品。
5-FU-rHSA-PEG-NPs具有改善的细胞毒性和药代动力学特性。因此，08小时和5-FU溶液的0.30±0.09小时。
5-FU-rHSA-PEG-NPs具有改善的细胞毒性和药代动力学特性。因此，必须将5-FU-rHSA-PEG-NPs进一步在严格环境下进行测试，以转化为临床产品。
