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Engineering polymeric aptamers for selective cytotoxicity.

ABSTRACT: Chemotherapy strategies thus far reported can result in both side effects and drug resistance. To address both of these issues at the cellular level, we report a molecular engineering strategy, which employs polymeric aptamers to induce selective cytotoxicity inside target cells. The polymeric aptamers, composed of both multiple cell-based aptamers and a high ratio of dye-labeled short DNA, exploit the target recognition capability of the aptamer, enhanced cell internalization via multivalent effects, and cellular disruption by the polymeric conjugate. Importantly, the polymer backbone built into the conjugate is cytotoxic only inside cells. As a result, selective cytotoxicity is achieved equally in both normal cancer cells and drug-resistant cells. Control assays have confirmed the nontoxicity of the aptamer itself, but they have also shown that the physical properties of the polymer backbone contribute to target cell cytotoxicity. Therefore, our approach may shed new light on drug design and drug delivery.

SUBMITTER: Yang L

PROVIDER: S-EPMC3190636 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Engineering polymeric aptamers for selective cytotoxicity.

Yang Liu L Meng Ling L Zhang Xiaobing X Chen Yan Y Zhu Guizhi G Liu Haipeng H Xiong Xiangling X Sefah Kwame K Tan Weihong W

Journal of the American Chemical Society 20110805 34

Chemotherapy strategies thus far reported can result in both side effects and drug resistance. To address both of these issues at the cellular level, we report a molecular engineering strategy, which employs polymeric aptamers to induce selective cytotoxicity inside target cells. The polymeric aptamers, composed of both multiple cell-based aptamers and a high ratio of dye-labeled short DNA, exploit the target recognition capability of the aptamer, enhanced cell internalization via multivalent ef ...[more]

PMID: 21702469

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Project description:We aim to discover diagnostic tools to detect phosphatidylserine (PS) externalization on apoptotic cell surface using PS binding aptamers, AAAGAC and TAAAGA, and hence to understand chemotherapy drug efficacy when inducing apoptosis into cancer cells. The entropic fragment-based approach designed aptamers have been investigated to inspect three aspects: lipid specificity in aptamers' membrane binding and bilayer physical properties-induced regulation of binding mechanisms, the apoptosis-induced cancer cell surface binding of aptamers, and the aptamer-induced cytotoxicity. The liposome binding assays show preferred membrane binding of aptamers due to presence of PS in predominantly phosphatidylcholine-contained liposomes. Two membrane stiffness reducing amphiphiles triton X-100 and capsaicin were found to enhance membrane's aptamer adsorption suggesting that bilayer physical properties influence membrane's adsorption of drugs. Microscopic images of fluorescence-tagged aptamer treated LoVo cells show strong fluorescence intensity only if apoptosis is induced. Aptamers find enhanced PS molecules to bind with on the surface of apoptotic over nonapoptotic cells. In cytotoxicity experiments, TAAAGA (over poor PS binding aptamer CAGAAAAAAAC) was found cytotoxic towards RBL cells due to perhaps binding with nonapoptotic externalized PS randomly and thus slowly breaching plasma membrane integrity. In these three experimental investigations, we found aptamers to act on membranes at comparable concentrations and specifically with PS binding manner. Earlier, we reported the origins of actions through molecular mechanism studies-aptamers interact with lipids using mainly charge-based interactions. Lipids and aptamers hold distinguishable charge properties, and hence, lipid-aptamer association follows distinguishable energetics due to electrostatic and van der Waals interactions. We discover that our PS binding aptamers, due to lipid-specific interactions, appear as diagnostic tools capable of detecting drug-induced apoptosis in cancer cells.

Dataset Information

Engineering polymeric aptamers for selective cytotoxicity.

Publications

Engineering polymeric aptamers for selective cytotoxicity.

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