A New Spin on Antibody-Drug Conjugates: Trastuzumab-Fulvestrant Colloidal Drug Aggregates Target HER2-Positive Cells.
While the formation of colloidal aggregates leads to artifacts in early drug discovery, their composition makes them attractive as nanoparticle formulations for targeted drug delivery as the entire nanoparticle is composed of drug. The typical transient stability of colloidal aggregates has inhibited exploiting this property. To overcome this limitation, we investigated a series of proteins to stabilize colloidal aggregates of the chemotherapeutic, fulvestrant, including the following: bovine serum albumin, a generic human immunoglobulin G, and trastuzumab, a therapeutic human epidermal growth factor receptor 2 antibody. Protein coronas reduced colloid size to <300 nm and improved their stability to over 48 h in both buffered saline and media containing serum protein. Unlike colloids stabilized with other proteins, trastuzumab-fulvestrant colloids were taken up by HER2 overexpressing cells and were cytotoxic. This new targeted formulation reimagines antibody-drug conjugates, delivering mM concentrations of drug to a cell.
Department of Chemical Engineering and Applied Chemistry, University of Toronto , 200 College Street, Toronto, Ontario, Canada M5S 3E5.|Institute of Biomaterials and Biomedical Engineering, University of Toronto , 164 College Street, Toronto, Ontario, Canada M5S 3G9.
Ahil N
AN
Ganesh
Department of Chemical Engineering and Applied Chemistry, University of Toronto , 200 College Street, Toronto, Ontario, Canada M5S 3E5.|Institute of Biomaterials and Biomedical Engineering, University of Toronto , 164 College Street, Toronto, Ontario, Canada M5S 3G9.
Christopher K
CK
McLaughlin
Department of Pharmaceutical Chemistry & Quantitative Biology Institute, University of California, San Francisco , 1700 Fourth Street, Mail Box 2550, San Francisco, California 94143, United States.
Da
D
Duan
Department of Pharmaceutical Chemistry & Quantitative Biology Institute, University of California, San Francisco , 1700 Fourth Street, Mail Box 2550, San Francisco, California 94143, United States.
Brian K
http://orcid.org/0000-0002-6098-7367
BK
Shoichet
Department of Chemical Engineering and Applied Chemistry, University of Toronto , 200 College Street, Toronto, Ontario, Canada M5S 3E5.|Institute of Biomaterials and Biomedical Engineering, University of Toronto , 164 College Street, Toronto, Ontario, Canada M5S 3G9.|Department of Chemistry, University of Toronto , 80 St. George Street, Toronto, Ontario, Canada M5S 3H6.
Molly S
http://orcid.org/0000-0003-1830-3475
MS
Shoichet
D000970:Antineoplastic Agents; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D004958:Estradiol / Q000031:analogs & derivatives / Q000737:chemistry*; D000077267:Fulvestrant; D006801:Humans; D053758:Nanoparticles; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab
D000970:Antineoplastic Agents; D004958:Estradiol; D000077267:Fulvestrant; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human
cell targeting; colloids; drug delivery; protein corona; self-assembly