Branched Multifunctional Polyether Polyketals: Variation of Ketal Group Structure Enables Unprecedented Control over Polymer Degradation in Solution and within Cells

Multifunctional biocompatible and biodegradable nanomaterials incorporating specific degradable linkages that respond to various stimuli and with defined degradation profiles are critical to the advancement of targeted nanomedicine. Herein we report, for the first time, a new class of multifunctiona...

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Bibliographic Details
Published in:	Journal of the American Chemical Society 2012-09, Vol.134 (36), p.14945-14957
Main Authors:	Shenoi, Rajesh A, Narayanannair, Jayaprakash K, Hamilton, Jasmine L, Lai, Benjamin F. L, Horte, Sonja, Kainthan, Rajesh K, Varghese, Jos P, Rajeev, Kallanthottathil G, Manoharan, Muthiah, Kizhakkedathu, Jayachandran N
Format:	Article
Language:	eng
Subjects:	Alcohols - chemical synthesis Alcohols - chemistry Animals Biocompatible Materials - chemistry Biocompatible Materials - metabolism Biocompatible Materials - pharmacology Blood Coagulation - drug effects Cell Survival - drug effects CHO Cells Cricetinae Dose-Response Relationship, Drug Endothelium, Vascular - cytology Endothelium, Vascular - drug effects Ethers - chemistry Ethers - metabolism Ethers - pharmacology Humans Hydrogen-Ion Concentration Hydrophobic and Hydrophilic Interactions Molecular Structure Polymers - chemistry Polymers - metabolism Polymers - pharmacology Solutions Structure-Activity Relationship Temperature
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Summary:	Multifunctional biocompatible and biodegradable nanomaterials incorporating specific degradable linkages that respond to various stimuli and with defined degradation profiles are critical to the advancement of targeted nanomedicine. Herein we report, for the first time, a new class of multifunctional dendritic polyether polyketals containing different ketal linkages in their backbone that exhibit unprecedented control over degradation in solution and within the cells. High-molecular-weight and highly compact poly(ketal hydroxyethers) (PKHEs) were synthesized from newly designed α-epoxy-ω-hydroxyl-functionalized AB2-type ketal monomers carrying structurally different ketal groups (both cyclic and acyclic) with good control over polymer properties by anionic ring-opening multibranching polymerization. Polymer functionalization with multiple azide and amine groups was achieved without degradation of the ketal group. The polymer degradation was controlled primarily by the differences in the structure and torsional strain of the substituted ketal groups in the main chain, while for polymers with linear (acyclic) ketal groups, the hydrophobicity of the polymer may play an additional role. This was supported by the log P values of the monomers and the hydrophobicity of the polymers determined by fluorescence spectroscopy using pyrene as the probe. A range of hydrolysis half-lives of the polymers at mild acidic pH values was achieved, from a few minutes to a few hundred days, directly correlating with the differences in ketal group structures. Confocal microscopy analyses demonstrated similar degradation profiles for PKHEs within live cells, as seen in solution and the delivery of fluorescent marker to the cytosol. The cell viability measured by MTS assay and blood compatibility determined by complement activation, platelet activation, and coagulation assays demonstrate that PKHEs and their degradation products are highly biocompatible. Taken together, these data demonstrate the utility this new class of biodegradable polymer as a highly promising candidate in the development of multifunctional nanomedicine.
ISSN:	0002-7863 1520-5126