title: Enhanced Cytotoxicity to Cancer Cells by Codelivery and Controlled Release of Paclitaxel-loaded Sirolimus-conjugated Albumin Nanoparticles.
abstract: Recently, it is suggested that mTOR signaling pathway is an important mediator in many cancers especially breast cancer. Therefore, effects of sirolimus as a mTOR inhibitor in breast cancer have been studied in combination with paclitaxel with or without controlled release effect. In this work, we prepared a water-soluble formulation of sirolimus-conjugated albumin nanoparticles loaded with paclitaxel, to study the effects of sirolimus concentration when it releases more later than paclitaxel in comparison with sirolimus-paclitaxel-loaded albumin nanoparticles. Also effects of paclitaxel loading on cytotoxic properties of nanoparticles were studied. Sirolimus was succinylated at 42-OH with enzymatic reaction of Candida antarctica lipase B, and then its carboxylic group was activated with EDC/NHS and conjugated to the lysine residues of albumin. Paclitaxel was loaded on albumin surface by nab technique in concentration range of 0-10 μg/mL. Sirolimus-conjugated nanoparticles with 0.01 μg/mL paclitaxel showed lowest cell viability of 44% while it was 53% for non-conjugated nanoparticles in MDA-MB-468 cell lines after 48 h (p-value = 0.003). In MCF-7 cell lines, sirolimus-conjugated nanoparticles with 0.1 μg/mL paclitaxel showed lowest cell viability of 35.69% while it was 48% for non-conjugated nanoparticles after 48 h (p-value = 0.03). We guess that when cancer cell lines arrest in G2-M by anticancer drugs like paclitaxel, Akt activates mTOR to make cells continue living, then inhibiting mTOR can enhance anticancer effects.
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran, Iran.
authors.forename: Hossein
authors.initials: H
authors.lastname: Behrouz
authors.affiliation: Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran, Iran.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Esfandyari-Manesh
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran, Iran.
authors.forename: Mohammad Kazem
authors.initials: MK
authors.lastname: Khoeeniha
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran, Iran.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Amini
authors.affiliation: Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran, Iran.
authors.forename: Behrang
authors.initials: B
authors.lastname: Shiri Varnamkhasti
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran, Iran.|Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran, Iran.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Atyabi
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran, Iran.|Nanotechnology Research Center, Faculty of Pharmacy, Tehran University of Medical Sciences, P.O. Box 14155-6451, Tehran, Iran.
authors.forename: Rassoul
authors.initials: R
authors.lastname: Dinarvand
mesh_terms: D000418:Albumins / Q000737:chemistry*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D002850:Chromatography, Gel; D003692:Delayed-Action Preparations; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D008854:Microscopy, Electron; D053758:Nanoparticles; D017239:Paclitaxel / Q000008:administration & dosage*; D020123:Sirolimus / Q000008:administration & dosage*; D017550:Spectroscopy, Fourier Transform Infrared; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: D000418:Albumins; D000972:Antineoplastic Agents, Phytogenic; D003692:Delayed-Action Preparations; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D017239:Paclitaxel; D020123:Sirolimus
keywords: codelivery; enhanced cytotoxicity; nanotechnology; paclitaxel; sirolimus