title: Docetaxel-carboxymethylcellulose nanoparticles target cells via a SPARC and albumin dependent mechanism.
abstract: Cellax, a polymer-docetaxel (DTX) conjugate that self-assembled into 120 nm particles, displayed significant enhancements in safety and efficacy over native DTX across a number of primary and metastatic tumor models. Despite these exciting preclinical data, the underlying mechanism of delivery of Cellax remains elusive. Herein, we demonstrated that serum albumin efficiently adsorbed onto the Cellax particles with a 4-fold increased avidity compared to native DTX, and the uptake of Cellax by cells was primarily driven by an albumin and SPARC (secreted protein acidic and rich in cysteine, an albumin binder) dependent internalization mechanism. In the SPARC-positive cells, a >2-fold increase in cellular internalization of Cellax was observed in the presence of albumin. In the SPARC-negative cells, no difference in Cellax internalization was observed in the presence or absence of albumin. Evaluation of the internalization mechanism using endocytotic inhibitors revealed that Cellax was internalized predominantly via a clathrin-mediated endocytotic mechanism. Upon internalization, it was demonstrated that Cellax was entrapped within the endo-lysosomal and autophagosomal compartments. Analysis of the tumor SPARC level with tumor growth inhibition of Cellax in a panel of tumor models revealed a positive and linear correlation (R(2) > 0.9). Thus, this albumin and SPARC-dependent pathway for Cellax delivery to tumors was confirmed both in vitro and in vivo.
authors.affiliation: Drug Delivery and Formulation, Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada.
authors.forename: Bryan
authors.initials: B
authors.lastname: Hoang
authors.affiliation: Drug Delivery and Formulation, Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada; Faculty of Engineering and Architectural Science, Ryerson University, Toronto, ON, Canada.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ernsting
authors.affiliation: Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Aniruddha
authors.initials: A
authors.lastname: Roy
authors.affiliation: Drug Delivery and Formulation, Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada.
authors.forename: Mami
authors.initials: M
authors.lastname: Murakami
authors.affiliation: Drug Delivery and Formulation, Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada.
authors.forename: Elijus
authors.initials: E
authors.lastname: Undzys
authors.affiliation: Drug Delivery and Formulation, Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada; Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada. Electronic address: shyh-dar.li@ubc.ca.
authors.forename: Shyh-Dar
authors.initials: SD
authors.lastname: Li
mesh_terms: D000418:Albumins / Q000737:chemistry*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000737:chemistry; D002266:Carboxymethylcellulose Sodium / Q000737:chemistry*; D002460:Cell Line; D000077143:Docetaxel; D004705:Endocytosis; D006801:Humans; D053758:Nanoparticles; D015676:Osteonectin / Q000737:chemistry*; D043823:Taxoids / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D000418:Albumins; D000972:Antineoplastic Agents, Phytogenic; D015676:Osteonectin; D043823:Taxoids; D000077143:Docetaxel; D002266:Carboxymethylcellulose Sodium
keywords: Albumin; Cellax; Docetaxel; Nanoparticle uptake; SPARC