title: Folic acid and trastuzumab conjugated redox responsive random multiblock copolymeric nanocarriers for breast cancer therapy: In-vitro and in-vivo studies.
abstract: The study represents synthesis, characterization and biological evaluation of redox responsive polymeric nanoparticles based on random multiblock copolymer for doxorubicin delivery in breast cancer. The random multiblock copolymer was synthesized via ring opening polymerization of lactide with polyethylene glycol to form triblock copolymer followed by isomerization polymerization of the triblock copolymer and 2-hydroxyethyl disulfide with the help of hexamethylene diisocynate in presence of dibutyltin dilaurate as a catalyst. Folic acid was conjugated to hydroxyl group from the multiblock polymer through DCC-NHS coupling. High drug loading content of ∼22% was achieved in the polymeric nanoparticles with size range of ∼110nm and polyethylene glycol fraction of ∼18% in the multiblock copolymer. Drug release profile confirmed the redox responsive behavior of polymeric nanoparticles with ∼72% drug release at pH 5.5 in presence of 10mM GSH as compared to ∼18% drug release at pH 7.4. In vitro cellular uptake studies showed ∼22% cellular uptake with dual (folic acid and trastuzumab) conjugated polymeric nanoparticles as compared to non-targeted polymeric nanoparticles. Fluorescence activated cell sorting (FACS) studies demonstrated higher apoptosis (∼80%) as compared to non-conjugated polymeric nanoparticles (20%) in MCF-7 cell line. In vivo studies showed 91% tumor regression in Ehrlich ascites tumor (EAT) as compared to free doxorubicin treated mice without showing any significant toxicity. Thus, it is envisaged that these redox responsive polymeric nanocarriers act as Trojan horses in cancer therapeutics.
authors.affiliation: Centre for Biomedical Engineering, Indian Institute of Technology Delhi, New Delhi 110016, India; Biomedical Engineering Unit, All India Institute of Medical Sciences, AIIMS, New Delhi 110029, India.
authors.forename: Arun
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Centre for Biomedical Engineering, Indian Institute of Technology Delhi, New Delhi 110016, India; Biomedical Engineering Unit, All India Institute of Medical Sciences, AIIMS, New Delhi 110029, India.
authors.forename: Shantanu V
authors.initials: SV
authors.lastname: Lale
authors.affiliation: Centre for Biomedical Engineering, Indian Institute of Technology Delhi, New Delhi 110016, India; Biomedical Engineering Unit, All India Institute of Medical Sciences, AIIMS, New Delhi 110029, India.
authors.forename: M R
authors.initials: MR
authors.lastname: Aji Alex
authors.affiliation: Centre for Polymer Science and Engineering, Indian Institute of Technology Delhi, New Delhi 110016, India.
authors.forename: Veena
authors.initials: V
authors.lastname: Choudhary
authors.affiliation: Centre for Biomedical Engineering, Indian Institute of Technology Delhi, New Delhi 110016, India; Biomedical Engineering Unit, All India Institute of Medical Sciences, AIIMS, New Delhi 110029, India. Electronic address: veenak_iitd@yahoo.com.
authors.forename: Veena
authors.initials: V
authors.lastname: Koul
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis; D001692:Biological Transport; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology*; D004337:Drug Carriers; D065546:Drug Liberation; D005260:Female; D005492:Folic Acid / Q000737:chemistry; D006801:Humans; D007279:Injections, Subcutaneous; D061986:MCF-7 Cells; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry / Q000648:ultrastructure; D009368:Neoplasm Transplantation; D010084:Oxidation-Reduction; D000068878:Trastuzumab / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D004317:Doxorubicin; D005492:Folic Acid; D000068878:Trastuzumab
keywords: Ehrlich’s ascites tumor; Multiblock copolymer; Redox sensitive nanoparticles; Trastuzumab