title: pH-Sensitive, N-ethoxybenzylimidazole (NEBI) bifunctional crosslinkers enable triggered release of therapeutics from drug delivery carriers.
abstract: This paper presents a pH-sensitive bifunctional crosslinker that enables facile conjugation of small molecule therapeutics to macromolecular carriers for use in drug delivery systems. This N-ethoxybenzylimidazole (NEBI) bifunctional crosslinker was designed to exploit mildly acidic, subcellular environments to trigger the release of therapeutics upon internalization in cells. We demonstrate that an analog of doxorubicin (a representative example of an anticancer therapeutic) conjugated to human serum albumin (HSA, a representative example of a macromolecular carrier) via this NEBI crosslinker can internalize and localize into acidic lysosomes of ovarian cancer cells. Fluorescence imaging and cell viability studies demonstrate that the HSA-NEBI-doxorubicin conjugate exhibited improved uptake and cytotoxic activity compared to the unconjugated doxorubicin analog. The pH-sensitive NEBI group was also shown to be relatively stable to biologically-relevant metal Lewis acids and to serum proteins, supporting that these bifunctional crosslinkers may be useful for constructing drug delivery systems that will be stable in biological fluids such as blood.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, MC 0358, La Jolla, CA 92093-0358, USA.
authors.forename: Alice
authors.initials: A
authors.lastname: Luong
authors.forename: Tawny
authors.initials: T
authors.lastname: Issarapanichkit
authors.forename: Seong Deok
authors.initials: SD
authors.lastname: Kong
authors.forename: Rina
authors.initials: R
authors.lastname: Fong
authors.forename: Jerry
authors.initials: J
authors.lastname: Yang
mesh_terms: D001562:Benzimidazoles / Q000737:chemistry*; D002021:Buffers; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003432:Cross-Linking Reagents / Q000737:chemistry*; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology*; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems; D004705:Endocytosis / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D006868:Hydrolysis / Q000187:drug effects; D007093:Imidazoles / Q000737:chemistry*; D058116:Lewis Acids / Q000737:chemistry; D008856:Microscopy, Fluorescence; D012709:Serum Albumin / Q000737:chemistry / Q000494:pharmacology; D012996:Solutions
chemical_list: D001562:Benzimidazoles; D002021:Buffers; D003432:Cross-Linking Reagents; D004337:Drug Carriers; D007093:Imidazoles; D058116:Lewis Acids; D012709:Serum Albumin; D012996:Solutions; D004317:Doxorubicin