Item Details

abstract

Mesoporous silica nanoparticles (MSNs) have a wide range of applications in the basic and biomedical sciences. Because of their unique pore structures and physicochemical properties, MSNs have recently attracted major attention as an inert carrier material in oncology drug formulations. In this dissertation, MSNs were prepared and suitably functionalized to serve as a chemically robust and biocompatible delivery platform for highly cytotoxic platinum-acridine anticancer agents. The first part of the thesis introduces new methodology for increasing the pore size of MSNs in a controlled manner. It was found that, in the presence of n-decane as a swelling agent and DMF as a co-solvent, large-pore MSNs of approximately 80–120 nm in diameter can be generated (transmission electron microscopy, TEM). In these materials, pores as large as 7.2 nm in diameter are formed, based on small-angle X-ray scattering (SAXS) and nitrogen physisorption measurements. These as-synthesized MSNs were further modified with covalently grafted carboxylate groups, which are able to coordinate with the platinum payload and allow its selective release in acidic microenvironments inside cancer cells. To improve the biocompatibility and colloidal stability of the materials, polyethylenglycol (PEG) polymer or a protective lipid bilayer were introduced using covalent grafting and non-covalent encapsulation procedures, respectively. The lipid-coated formulation generated from the large-pore material, MSNLP, showed (i) a high loading capacity for the dicationic, hydrophilic hybrid agent [PtCl(en)(N-[acridin-9-ylaminoethyl]-N-methylpropionamidine)] dinitrate salt (P1A1, en = ethane-1,2-diamine), (ii) virtually complete retention of payload at neutral pH in a high-chloride buffer mimicking circulation, and (iii) excellent colloidal stability (dynamic light scattering, DLS). The final formulations were further characterized by SAXS, gas sorption measurements, thermogravimetric analysis (TGA), Fourier-transform infrared spectroscopy (FT-IR), TEM, scanning TEM (STEM), and energy-dispersive spectroscopy (EDS). In acidic media mimicking the pH inside the cells’ lysosomes, rapid, burst-like release of P1A1 from the nanoparticles is observed (spectrophotometric assay). The carboxylate-modified, lipid bilayer-coated form of the nanoparticles (P1A1@MSN-COOH-LIP) containing 60 wt.% drug caused efficient S phase cell cycle arrest (flow cytometry) and inhibited cell proliferation at submicromolar concentrations in pancreatic cancer cells (PANC1 and BxPC3) similar to unencapsulated P1A1. The most striking feature of the nanoparticles after internalization into BxPC3 cells was their ability to prevent lysosomal escape of P1A1 in the cytoplasm and promote trafficking of the payload directly to the nucleus (confocal fluorescence microscopy). The results of this study suggest that the newly developed MSN-based formulation should be an ideal delivery platform for platinum-acridine anticancer agents and deserves further evaluation in animals.

subject

anticancer drug delivery

large pore

liposome encapsulation

mesoporous silica nanoparticles

PEGylation

platinum-acridines

contributor

Zheng, Ye (author)

Bierbach, Ulrich (committee chair)

Cho, Samuel S (committee member)

Welker, Mark E (committee member)

Gross, Michael D (committee member)

Hinze, Willie L (committee member)

date

2017-01-14T09:35:19Z (accessioned)

2018-01-13T09:30:08Z (available)

2016 (issued)

degree

Chemistry (discipline)

embargo

2018-01-13 (terms)

identifier

http://hdl.handle.net/10339/64177 (uri)

language

en (iso)

publisher

Wake Forest University

title

PREPARATION AND EVALUATION OF MESOPOROUS SILICA NANOPARTICLES FOR PLATINUM-ACRIDINE ANTICANCER DRUG DELIVERY

type

Dissertation