Programmable Nanomaterials for Detoxification

Open Access
Author:
Chen, Niancao
Graduate Program:
Bioengineering
Degree:
Doctor of Philosophy
Document Type:
Dissertation
Date of Defense:
December 04, 2014
Committee Members:
  • Yong Wang, Dissertation Advisor
  • Yong Wang, Committee Chair
  • Jian Yang, Committee Member
  • Christine Dolan Keating, Committee Member
  • Manish Kumar, Committee Member
Keywords:
  • Aptamer
  • Nanoparticle
  • detoxification
Abstract:
Exogenous chemicals (e.g., drugs) and endogenous signaling molecules (e.g., growth factors) are important for the treatment of human diseases and the maintenance of a normal metabolism in the body. However, they can cause severe or fatal toxicity problems when their concentrations in the body exceed certain ranges1–3. To mitigate their toxic effects on the body, a myriad of antidotes have been developed. Of them, nanoparticles (e.g., liposomes) have recently attracted the most attention because nanoparticles can act as a sink to sequester toxic molecules more efficiently 4,5. Despite their promise, most nanoparticles have relatively low affinity in sequestering target molecules and slow sequestration rates. Moreover, currently available nanoparticle antidotes cannot be actively regulated to control their capability of sequestering target molecules. As a result, when nanoparticles are applied to sequester endogenous signaling molecules, these molecules may be over eliminated, which can also cause severe effects or even fatality. Thus, it is important that nanoparticle antidotes provide molecularly controllable target sequestration, which has never been studied before. This dissertation research explores the concept of bidirectional molecular recognition control for the development of an open, programmable nanoscale antidote. This nanoscale antidote can not only sequester target molecules effectively and rapidly, but also release target molecules via molecular interactions on demand. To construct the antidote, DNA oligonucleotides were used as programmable building blocks and affinity ligands (i.e., nucleic acid aptamer) for the synthesis of both linear and branched affinity DNA polymers (DPs). A magnetic nanoparticle was used as a nanoscaffold to support the growth of the DPs on its surface. Each repeating unit of the DP has the capability of target sequestration. The sequestration functionality of this programmable nanoparticle antidote was evaluated by using both a small molecule drug and large molecule protein. This novel antidote was also examined by evaluating its capabilities in mitigating the biological effects of the drug and the protein. Moreover the reversing of target sequestration via molecular regulation was validated. This dissertation has four major chapters. In Chapter 1, current strategies for developing nanoparticle-based antidotes are systematically reviewed. In Chapter 2, the synthesis of affinity DNA polymer-functionalized nanoparticles is introduced. In Chapter 3, the functionalities of the programmable antidote for detoxification is demonstrated in vitro. In Chapter 4, the ability to program the function of the antidote via molecular regulation is validated. The data suggest that this antidote can sequester both small molecules and large proteins. Importantly, this antidote can be programmed via strand displacement to control the molecular sequestration. The success of this study has opened a new avenue for the development of antidotes for safe and effective detoxification of either endogenous or exogenous molecules. Moreover, the programmable antidote explored in this dissertation research holds great potential as a smart nanomaterial for other biomedical applications, such as molecularly regulated drug delivery.