Degree Type

Dissertation

Date of Award

2009

Degree Name

Doctor of Philosophy

Department

Chemistry

First Advisor

Victor S. Lin

Abstract

Mesoporous silica nanoparticles (MSNs) are a highly promising platform for intracellular controlled release of drugs and biomolecules. Despite that the application of MSNs in the field of intracellular drug delivery is still at its infancy very exciting breakthroughs have been achieved in the last years. A general review of the most recent progress in this area of research is presented, including a description of the latest findings on the pathways of entry into live mammalian cells together with the intracellular trafficking, a summary on the contribution of MSNs to the development of site-specific drug delivery systems, a report on the biocompatibility of this material in vitro and in vivo, and a discussion on the most recent breakthroughs in the synthesis and application of stimuli-responsive mesoporous silica-based delivery vehicles.

A gold nanoparticles (AuNPs)-capped MSNs-based intracellular photoinduced drug delivery system (PR-AuNPs-MSNs) for the controlled release of anticancer drug inside of human fibroblast and liver cells was synthesized and characterized. We found that the mesoporous channels of MSNs could be efficiently capped by the photoresponsive AuNPs without leaking the toxic drug, paclitaxel, inside of human cells. Furthermore, we demonstrated that the cargo-release property of this PR-AuNPs-MSNs system could be easily photo-controlled under mild and biocompatible conditions in vitro.

In collaboration with Renato Mortera (a visiting student from Italy), a MSNs based intracellular delivery system for controlled release of cell membrane impermeable cysteine was developed. A large amount of cysteine molecules were covalently attached to the silica surface of MSNs through cleavable disulfide linkers. These cysteine-containing nanoparticles were efficiently endocytosed by human cervical cancer cells HeLa. These materials exhibit 450 times higher cell growth inhibition capability than that of the conventional N-acetylcysteine prodrug.

The ability to functionalize the surface of the MSNs with organic groups was used as a way to incorporate functional molecules that can interact with intracellular structures. A series of oligonucleotides intercalating (propidium) derivative functionalized MSNs (PAP-LP-MSNs and AP-PAP-MSNs) materials were synthesized. We selectively decorated the exterior particle surface of PAP-LP-MSN and the interior pore surface of AP-PAP-MSN with the oligonucleotide intercalating functionality. We observed that these materials are internalized by HeLa cells despite that the propidium group is known by its cell membrane impermeable properties. By confocal microscopy and flow cytometry, we demonstrated that indeed PAP-LP-MSNs were able to bind to cytoplasmic oligonucleotides; such as messenger RNA, resulting in severe cell growth inhibition. In contrast, the cytotoxicity of AP-PAP-MSN, where the same oligonucleotide intercalating molecules were anchored inside the pores, was significantly lowered upon the endocytosis by HeLa cells. The results obtained prove that the biocompatibility and cell membrane trafficking properties of MSNs could be modified by selective functionalization of the two different surfaces (exterior particle and interior pore surfaces) and morphology control of MSNs.

Copyright Owner

Juan Luis Vivero-escoto

Language

en

Date Available

2012-04-30

File Format

application/pdf

File Size

170 pages

Included in

Chemistry Commons

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