title: Paclitaxel-conjugated PAMAM dendrimers adversely affect microtubule structure through two independent modes of action.
abstract: Paclitaxel (Taxol) is an anticancer drug that induces mitotic arrest via microtubule hyperstabilization but causes side effects due to its hydrophobicity and cellular promiscuity. The targeted cytotoxicity of hydrophilic paclitaxel-conjugated polyamidoamine (PAMAM) dendrimers has been demonstrated in cultured cancer cells. Mechanisms of action responsible for this cytotoxicity are unknown, that is, whether the cytotoxicity is due to paclitaxel stabilization of microtubules, as is whether paclitaxel is released intracellularly from the dendrimer. To determine whether the conjugated paclitaxel can bind microtubules, we used a combination of ensemble and single microtubule imaging techniques in vitro. We demonstrate that these conjugates adversely affect microtubules by (1) promoting the polymerization and stabilization of microtubules in a paclitaxel-dependent manner, and (2) bundling preformed microtubules in a paclitaxel-independent manner, potentially due to protonation of tertiary amines in the dendrimer interior. Our results provide mechanistic insights into the cytotoxicity of paclitaxel-conjugated PAMAM dendrimers and uncover unexpected risks of using such conjugates therapeutically.
authors: Cellular and Molecular Biology Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Erika N
authors: EN
authors: Cline
authors: Ming-Hsin
authors: MH
authors: Li
authors: Seok Ki
authors: SK
authors: Choi
authors: Jeffrey F
authors: JF
authors: Herbstman
authors: Neha
authors: N
authors: Kaul
authors: Edgar
authors: E
authors: Meyhöfer
authors: Georgios
authors: G
authors: Skiniotis
authors: James R
authors: JR
authors: Baker
authors: Ronald G
authors: RG
authors: Larson
authors: Nils G
authors: NG
authors: Walter
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000009:adverse effects* / Q000737:chemistry*; D002417:Cattle; D050091:Dendrimers / Q000009:adverse effects* / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods; D008856:Microscopy, Fluorescence; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry; D017239:Paclitaxel / Q000009:adverse effects* / Q000737:chemistry*; D058105:Polymerization; D014404:Tubulin / Q000302:isolation & purification / Q000378:metabolism
chemical_list: D001672:Biocompatible Materials; D050091:Dendrimers; C104700:PAMAM Starburst; D014404:Tubulin; D017239:Paclitaxel
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