title: Dual Drug Conjugate Loaded Nanoparticles for the Treatment of Cancer.
abstract: Two antineoplastic agents, Imatinib (IM) and 5-Fluorouracil (FU) were conjugated by hydrolysable linkers through an amide bond and entrapped in polymeric Human Serum Albumin (HSA) nanoparticles. The presence of dual drugs in a common carrier has the advantage of reaching the site of action simultaneously and acting at different phases of the cell cycle to arrest the growth of cancer cells before they develop chemoresistance. The study has demonstrated an enhanced anticancer activity of the conjugate, and conjugate loaded stealth HSA nanoparticles (NPs) in comparison to the free drug in A-549 human lung carcinoma cell line and Zebra fish embryos (Danio rerio). Hydrolysability of the conjugate has also been demonstrated with complete hydrolysis being observed after 12 h. In vivo pharmacodynamics study in terms of tumor volume and pharmacokinetics in mice for conjugate (IM-SC-FU) and conjugate loaded nanoparticles showed significant anti-cancer activity. The other parameters evaluated were particle size (86nm), Poly Dispersive Index (PDI) (0.209), zeta potential (-49mV), drug entrapment efficiency (96.73%) and drug loading efficiency (89%). Being in stealth mode gives the potential for the NPs to evade Reticulo-Endothelial system (RES), achieve passive targeting by Enhanced Permeation Retention (EPR) effect with controlled release of the therapeutic agent. As the conjugate cleaves into individual drugs in the tumor environment, this promises better suppression of cancer chemoresistance by delivering dual drugs with different modes of action at the same site, thereby synergistically inhibiting the growth of cancerous tissue.
authors.forename: Megha Shyam
authors.initials: MS
authors.lastname: Matlapudi
authors.forename: Afrasim
authors.initials: A
authors.lastname: Moin
authors.forename: Raghavender
authors.initials: R
authors.lastname: Medishetti
authors.forename: K
authors.initials: K
authors.lastname: Rajendra
authors.forename: Ashok M
authors.initials: AM
authors.lastname: Raichur
authors.affiliation: Department of Pharmaceutical Chemistry, JSS College of Pharmacy-Mysore, JSS University, S.S. Nagar, Mysore- 570015, Karnataka, India. brprashanthkumar@jssuni.edu.in.
authors.forename: B R Prashantha
authors.initials: BR
authors.lastname: Kumar
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003692:Delayed-Action Preparations; D004337:Drug Carriers / Q000737:chemistry; D016503:Drug Delivery Systems; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D000068877:Imatinib Mesylate / Q000008:administration & dosage; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D053758:Nanoparticles; D010316:Particle Size; D012709:Serum Albumin / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays; D015027:Zebrafish
chemical_list: D003692:Delayed-Action Preparations; D004337:Drug Carriers; D012709:Serum Albumin; D000068877:Imatinib Mesylate; D005472:Fluorouracil