title: Functionalized Lipid-Polymer Hybrid Nanoparticles Mediated Codelivery of Methotrexate and Aceclofenac: A Synergistic Effect in Breast Cancer with Improved Pharmacokinetics Attributes.
abstract: 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.
authors.affiliation: University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Studies, Panjab University , Chandigarh 160014, India.
authors.forename: Neeraj K
authors.initials: NK
authors.lastname: Garg
authors.affiliation: Institute of Science, Nirma University , SG Highway, Ahmedabad, Gujarat 382481 India.
authors.forename: Rajeev K
authors.initials: RK
authors.lastname: Tyagi
authors.affiliation: University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Studies, Panjab University , Chandigarh 160014, India.
authors.forename: Gajanand
authors.initials: G
authors.lastname: Sharma
authors.affiliation: University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Studies, Panjab University , Chandigarh 160014, India.
authors.forename: Ashay
authors.initials: A
authors.lastname: Jain
authors.affiliation: University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Studies, Panjab University , Chandigarh 160014, India.|UGC-Centre of Excellence in Applications of Nanomaterials, Nanoparticles & Nanocomposites (Biomedical Sciences), Panjab University , Chandigarh 160 014, India.
authors.forename: Bhupinder
authors.initials: B
authors.lastname: Singh
authors.affiliation: Centre for Pharmaceutical Nanotechnology, Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER) , Sector 67, SAS Nagar, Mohali, Punjab 160062, India.
authors.forename: Sanyog
authors.initials: S
authors.lastname: Jain
authors.affiliation: University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Studies, Panjab University , Chandigarh 160014, India.
authors.forename: O P
authors.initials: OP
authors.lastname: Katare
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004008:Diclofenac / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008055:Lipids / Q000737:chemistry*; D061986:MCF-7 Cells; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D008727:Methotrexate / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; D008055:Lipids; D011108:Polymers; D014409:Tumor Necrosis Factor-alpha; D004008:Diclofenac; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D020781:Matrix Metalloproteinase 1; C056498:aceclofenac; D008727:Methotrexate
keywords: Cox-2; MMP-1; aceclofenac; breast cancer targeting; coencapsulation; fucose; lipid−polymer hybrid nanoparticles; methotrexate