title: Cell-Penetrating, Guanidinium-Rich Oligophosphoesters: Effective and Versatile Molecular Transporters for Drug and Probe Delivery.
abstract: The design, synthesis, and biological evaluation of a new family of highly effective cell-penetrating molecular transporters, guanidinium-rich oligophosphoesters, are described. These unique transporters are synthesized in two steps, irrespective of oligomer length, by the organocatalytic ring-opening polymerization (OROP) of 5-membered cyclic phospholane monomers followed by oligomer deprotection. Varying the initiating alcohol results in a wide variety of cargo attachment strategies for releasable or nonreleasable transporter applications. Initiation of oligomerization with a fluorescent probe produces, upon deprotection, a transporter-probe conjugate that is shown to readily enter multiple cell lines in a dose-dependent manner. These new transporters are superior in cell uptake to previously studied guanidinium-rich oligocarbonates and oligoarginines, showing over 2-fold higher uptake than the former and 6-fold higher uptake than the latter. Initiation with a protected thiol gives, upon deprotection, thiol-terminated transporters which can be thiol-click conjugated to a variety of probes, drugs and other cargos as exemplified by the conjugation and delivery of the model probe fluorescein-maleimide and the medicinal agent paclitaxel (PTX) into cells. Of particular significance given that drug resistance is a major cause of chemotherapy failure, the PTX-transporter conjugate, designed to evade Pgp export and release free PTX after cell entry, shows efficacy against PTX-resistant ovarian cancer cells. Collectively this study introduces a new and highly effective class of guanidinium-rich cell-penetrating transporters and methodology for their single-step conjugation to drugs and probes, and demonstrates that the resulting drug/probe-conjugates readily enter cells, outperforming previously reported guanidinium-rich oligocarbonates and peptide transporters.
authors.affiliation: Department of Chemistry and ‡Department of Chemical and Systems Biology, Stanford University , Stanford, California 94305, United States.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: McKinlay
authors.affiliation: Department of Chemistry and ‡Department of Chemical and Systems Biology, Stanford University , Stanford, California 94305, United States.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Waymouth
authors.affiliation: Department of Chemistry and ‡Department of Chemical and Systems Biology, Stanford University , Stanford, California 94305, United States.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Wender
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D005456:Fluorescent Dyes / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D019791:Guanidine / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D018613:Microscopy, Confocal; D063065:Organophosphonates / Q000008:administration & dosage* / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D005456:Fluorescent Dyes; D063065:Organophosphonates; D019791:Guanidine; D017239:Paclitaxel