title: Surface engineered nanostructured lipid carriers for targeting MDR tumor: Part I. Synthesis, characterization and in vitro investigation.
abstract: Over expression of P-glycoprotein (P-gp) in cancer cells often results in highly aggressive, multi-drug resistant (MDR) phenotype. Such tumors are very difficult to treat with conventional therapy and often lead to failure of the treatment. In this work, we fabricated surface engineered hybrid lipid nanoparticles grafted with novel AL-HA polymer by mineralization technique. AL-HA graft polymer was prepared by covalent conjugation of alendronate sodium and hyaluronic acid. Compritol ATO 888 and capmule MCM C8 hybrid lipid mix was employed to prepare irinotecan containing nanostructured lipid carrier (NLC) by using functional excipients with P-gp inhibition activity. AL-HA was successfully grafted over NLC-Ir (uncoated irinotecan loaded NLC) by calcium-assisted mineralization. HA-NLC-Ir (hyaluronic acid coated irinotecan loaded NLC) particles have a nanoscale size of 386±2.2 nm along with a zeta potential value of 19.7±1.2 mV. NLC-Ir as well as HA-NLC-Ir showed a slow and sustained drug release. In vitro cell line studies performed on HT-29 and Colo-320 colon cancer cells revealed a reduced IC50 even in MDR cells. Flowcytometry studies demonstrated the capability of the developed nanocarriers to deliver the P-gp substrate moieties in MDR cancer cells. Furthermore, the targeting potential of HA-NLC was confirmed by CLSM studies. The cell line studies also revealed that NLC formulation had a potential of inhibiting P-gp by affecting ATPase activity and MDR1 gene expression.
authors.affiliation: Nano Research Lab, Department of Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard, New Delhi 110062, India.
authors.forename: Lalit Mohan
authors.initials: LM
authors.lastname: Negi
authors.affiliation: Nano Research Lab, Department of Pharmaceutics, Faculty of Pharmacy, Jamia Hamdard, New Delhi 110062, India. Electronic address: stalegaonkar@gmail.com.
authors.forename: Sushama
authors.initials: S
authors.lastname: Talegaonkar
authors.affiliation: Preclinical Department, Dabur Research Foundation, Ghaziabad 201010, Uttar Pradesh, India.
authors.forename: Manu
authors.initials: M
authors.lastname: Jaggi
authors.affiliation: Nano Biotechnology Lab, Department of Zoology, K.M. College, Delhi University, Delhi 110007, India.
authors.forename: Anita Kamra
authors.initials: AK
authors.lastname: Verma
authors.affiliation: Department of Cell Biology, Dabur Research Foundation, Ghaziabad 201010, Uttar Pradesh, India.
authors.forename: Ritu
authors.initials: R
authors.lastname: Verma
authors.affiliation: Department of Cell Biology, Dabur Research Foundation, Ghaziabad 201010, Uttar Pradesh, India.
authors.forename: Sheetal
authors.initials: S
authors.lastname: Dobhal
authors.affiliation: Nano Biotechnology Lab, Department of Zoology, K.M. College, Delhi University, Delhi 110007, India.
authors.forename: Vijay
authors.initials: V
authors.lastname: Kumar
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry; D019386:Alendronate / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002166:Camptothecin / Q000031:analogs & derivatives / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D005434:Flow Cytometry; D019073:HT29 Cells; D006801:Humans; D018960:Hyaluronan Receptors / Q000737:chemistry; D006820:Hyaluronic Acid / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D000077146:Irinotecan; D008055:Lipids / Q000737:chemistry*; D049329:Nanostructures / Q000737:chemistry*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D004337:Drug Carriers; D018960:Hyaluronan Receptors; D008055:Lipids; D000077146:Irinotecan; D006820:Hyaluronic Acid; D019386:Alendronate; D002166:Camptothecin
keywords: CD-44; Hyaluronic acid; In vitro; Irinotecan; NLC; P-glycoprotein