title: Novel ZnO hollow-nanocarriers containing paclitaxel targeting folate-receptors in a malignant pH-microenvironment for effective monitoring and promoting breast tumor regression.
abstract: Low pH in the tumor micromilieu is a recognized pathological feature of cancer. This attribute of cancerous cells has been targeted herein for the controlled release of chemotherapeutics at the tumour site, while sparing healthy tissues. To this end, pH-sensitive, hollow ZnO-nanocarriers loaded with paclitaxel were synthesized and their efficacy studied in breast cancer in vitro and in vivo. The nanocarriers were surface functionalized with folate using click-chemistry to improve targeted uptake by the malignant cells that over-express folate-receptors. The nanocarriers released ~75% of the paclitaxel payload within six hours in acidic pH, which was accompanied by switching of fluorescence from blue to green and a 10-fold increase in the fluorescence intensity. The fluorescence-switching phenomenon is due to structural collapse of the nanocarriers in the endolysosome. Energy dispersion X-ray mapping and whole animal fluorescent imaging studies were carried out to show that combined pH and folate-receptor targeting reduces off-target accumulation of the nanocarriers. Further, a dual cell-specific and pH-sensitive nanocarrier greatly improved the efficacy of paclitaxel to regress subcutaneous tumors in vivo. These nanocarriers could improve chemotherapy tolerance and increase anti-tumor efficacy, while also providing a novel diagnostic read-out through fluorescent switching that is proportional to drug release in malignant tissues.
authors.affiliation: Department of Chemistry, Indian Institute of Technology, Kharagpur, West Bengal, 721302, India.|Department of Pharmacology, Dalhousie Medicine New Brunswick, Dalhousie University, New Brunswick, Canada.
authors.forename: Nagaprasad
authors.initials: N
authors.lastname: Puvvada
authors.affiliation: School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, West Bengal, 721302, India.
authors.forename: Shashi
authors.initials: S
authors.lastname: Rajput
authors.affiliation: School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, West Bengal, 721302, India.
authors.forename: B N Prashanth
authors.initials: BNP
authors.lastname: Kumar
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine; Richmond, VA 23298, USA.
authors.forename: Siddik
authors.initials: S
authors.lastname: Sarkar
authors.affiliation: Department of Chemistry, Indian Institute of Technology, Kharagpur, West Bengal, 721302, India.
authors.forename: Suraj
authors.initials: S
authors.lastname: Konar
authors.affiliation: Department of Pharmacology, Dalhousie Medicine New Brunswick, Dalhousie University, New Brunswick, Canada.
authors.forename: Keith R
authors.initials: KR
authors.lastname: Brunt
authors.affiliation: Department of Chemical and Life Science Engineering, Virginia Commonwealth University, Richmond, VA 23238, USA.
authors.forename: Raj R
authors.initials: RR
authors.lastname: Rao
authors.affiliation: Department of Clinical Cancer Prevention and Systems Biology, University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Abhijit
authors.initials: A
authors.lastname: Mazumdar
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine; Richmond, VA 23298, USA.|VCU Institute of Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA 23238, USA.|VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA 23238, USA.
authors.forename: Swadesh K
authors.initials: SK
authors.lastname: Das
authors.affiliation: Central Research Facility, Indian Institute of Technology, Kharagpur, West Bengal, 721302, India.
authors.forename: Ranadhir
authors.initials: R
authors.lastname: Basu
authors.affiliation: Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine; Richmond, VA 23298, USA.|VCU Institute of Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA 23238, USA.|VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA 23238, USA.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
authors.affiliation: School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, West Bengal, 721302, India.
authors.forename: Mahitosh
authors.initials: M
authors.lastname: Mandal
authors.affiliation: Department of Chemistry, Indian Institute of Technology, Kharagpur, West Bengal, 721302, India.
authors.forename: Amita
authors.initials: A
authors.lastname: Pathak
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry* / Q000633:toxicity; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018450:Disease Progression; D004337:Drug Carriers / Q000737:chemistry*; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D053768:Metal Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D017239:Paclitaxel / Q000008:administration & dosage / Q000737:chemistry* / Q000633:toxicity; D014183:Transplantation, Heterologous; D015034:Zinc Oxide / Q000737:chemistry*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D017239:Paclitaxel; D015034:Zinc Oxide