Garg Neeraj K, Tyagi Rajeev K, Sharma Gajanand, Jain Ashay, Singh Bhupinder, Jain Sanyog, Katare O P
University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Studies, Panjab University , Chandigarh 160014, India.
Institute of Science, Nirma University , SG Highway, Ahmedabad, Gujarat 382481 India.
Mol Pharm. 2017 Jun 5;14(6):1883-1897. doi: 10.1021/acs.molpharmaceut.6b01148. Epub 2017 May 3.
The present study was aimed to coencapsulate methotrexate (MTX) and aceclofenac (ACL) in fucose anchored lipid-polymer hybrid nanoparticles (Fu-LPHNPs) to achieve target specific and controlled delivery for developing therapeutic interventions against breast cancer. The effective combination therapy requires coadministration of drugs to achieve synergistic effect on tumor with minimum adverse effects. Present study investigates the potential of codelivery of MTX and ACL through LPHNPs in MCF-7 and triple negative breast cancer cells (MDA-MB-231). We obtained LPHNPs in the nanosize range (<150 nm) with better particle size distribution (<0.3). The entrapment and loading efficiency of MTX and ACL was calculated as 85-90% and 10-12%, respectively. The coumarin-6 LPHNP formulations showed rapid internalization within 2 h incubation with MCF-7 and MDA-MB-231 cells. With 8-10 times, greater bioavailability of drug-loaded LPHNPs than free MTX and ACL was obtained. Also, antitumor efficacy of MTX- and ACL-loaded LPHNPs was determined on DMBA-induced experimental breast cancer mouse model. This model showed better control over tumor growth with MTX- and ACL-loaded LPHNPs than the combination of MTX and ACL or MTX alone. ACL-loaded LPHNPs showed prophylactic and anticancer activity in DMBA-induced mouse model at higher dose (10 mg/kg). ACL-LPHNPs confer synergistic anticancer effect when administered in combination with MTX. In conclusion, ACL enhances the therapeutic and anticancer efficacy of MTX, when coencapsulated into fucose-anchored LPHNPs, as confirmed by cell viability and serum angiogenesis (IL-6, TNF-α, IL-1β, COX2, and MMP1) at both transcript and proteome level.
本研究旨在将甲氨蝶呤（MTX）和醋氯芬酸（ACL）共包封于岩藻糖锚定的脂质-聚合物杂化纳米粒（Fu-LPHNPs）中，以实现靶向特异性和可控递送，从而开发针对乳腺癌的治疗干预措施。有效的联合治疗需要同时给药以在肿瘤上实现协同效应并使不良反应最小化。本研究调查了通过LPHNPs在MCF-7和三阴性乳腺癌细胞（MDA-MB-231）中共递送MTX和ACL的潜力。我们获得了纳米尺寸范围（<150 nm）且粒径分布更好（<0.3）的LPHNPs。MTX和ACL的包封率和载药效率分别计算为85 - 90%和10 - 12%。香豆素-6 LPHNP制剂在与MCF-7和MDA-MB-231细胞孵育2小时内显示出快速内化。载药LPHNPs的生物利用度比游离MTX和ACL高8 - 10倍。此外，在二甲基苯并蒽（DMBA）诱导的实验性乳腺癌小鼠模型上测定了载MTX和ACL的LPHNPs的抗肿瘤功效。该模型显示，与MTX和ACL联合使用或单独使用MTX相比，载MTX和ACL的LPHNPs对肿瘤生长的控制更好。高剂量（10 mg/kg）的载ACL的LPHNPs在DMBA诱导的小鼠模型中显示出预防和抗癌活性。ACL-LPHNPs与MTX联合给药时具有协同抗癌作用。总之，如在转录组和蛋白质组水平上通过细胞活力和血清血管生成（IL-6、TNF-α、IL-1β、COX2和MMP1）所证实的，当共包封于岩藻糖锚定的LPHNPs中时，ACL增强了MTX的治疗和抗癌功效。
