Paclitaxel-Conjugated PAMAM Dendrimers Adversely Affect Microtubule Structure through Two Independent Modes of Action

• Published in: Biomacromolecules Vol. 14; no. 3; pp. 654 - 664
• Main Authors: Cline, Erika N, Li, Ming-Hsin, Choi, Seok Ki, Herbstman, Jeffrey F, Kaul, Neha, Meyhöfer, Edgar, Skiniotis, Georgios, Baker, James R, Larson, Ronald G, Walter, Nils G
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 11.03.2013
• Subjects: Animals; Antineoplastic agents; Applied sciences; Biocompatible Materials - adverse effects; Biocompatible Materials - chemistry; Biological and medical sciences; Biological properties; Cattle; Chemotherapy; Dendrimers - adverse effects; Dendrimers - chemistry; Drug Delivery Systems - methods; Exact sciences and technology; Medical sciences; Microscopy, Fluorescence; Microtubules - drug effects; Microtubules - metabolism; Nanoparticles - chemistry; Organic polymers; Paclitaxel - adverse effects; Paclitaxel - chemistry; Pharmacology. Drug treatments; Physicochemistry of polymers; Polymerization; Properties and characterization; Tubulin - isolation & purification; Tubulin - metabolism; Antineoplastic agent; Dendrimer; Branched polymer; Control release polymer; Aromatic polymer; Drug carrier; Prodrug; Experimental study; In vitro; Amidoamine polymer; Aliphatic polymer; Microtubule; Mechanism of action; Antimitotic; Tumor cell
• ISSN: 1525-7797; 1526-4602
• DOI: 10.1021/bm301719b

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.