Designer Mesoporous Silica Nano-carriers for Hydrophobic Drug Delivery with Enhanced Bioavailability

Jambhrunkar, Siddharth (2014). Designer Mesoporous Silica Nano-carriers for Hydrophobic Drug Delivery with Enhanced Bioavailability PhD Thesis, Australian Institute for Bioengineering and Nanotechnology, The University of Queensland. doi:10.14264/uql.2014.409

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Author Jambhrunkar, Siddharth
Thesis Title Designer Mesoporous Silica Nano-carriers for Hydrophobic Drug Delivery with Enhanced Bioavailability
School, Centre or Institute Australian Institute for Bioengineering and Nanotechnology
Institution The University of Queensland
DOI 10.14264/uql.2014.409
Publication date 2014-10-17
Thesis type PhD Thesis
Open Access Status Other
Supervisor Chengzhong Yu
Wenyi Gu
Liliana Endo-Munoz
Total pages 148
Language eng
Subjects 1007 Nanotechnology
Formatted abstract
Since the discovery of mesoporous silica nanoparticles (MSNs) by Mobil’s researchers in 1992, it has aroused keen interest for its application in catalysis, adsorbent, and many more owing to its structural characteristics of high surface area, possibility of surface functionalization and adjustable pore size. It was in the last decade when MSNs were first reported for its application in drug delivery and since then researchers are exploring possibilities of MSNs to resolve the challenges in the pharmaceutical sector.

More than 40% of pharmaceutical drug candidates emerging from high throughput screening process are hydrophobic possessing low aqueous solubility and hence low bioavailability. These drug molecules are highly potent but, cannot be formulated as an effective formulation owing to its low aqueous solubility which hinders its clinical application. This raises a huge challenge for pharmaceutical scientists to enhance the aqueous solubility of hydrophobic drugs. Reducing the drug particle size can enhance the solubility according to the Ostwald–Freundlich equation. However, it has been difficult to downsize the drug particle below 20 nm with the existing technologies, a regime in which a dramatic increase in solubility is expected.

This research work seeks to overcome the limitations by enhancing aqueous solubility of hydrophobic drug molecules using MSNs. A simple and novel method have been developed wherein the pore size of MSNs can be systematically adjusted in a stepwise manner at step precision of angstrom scale to obtain a series of MSNs with controllable pore size (1-10 nm). By loading drug molecules inside the pores of MSNs, the drug particle sizes can be confined to the pore size. We hypothesize that, there exists an optimized pore size for a given hydrophobic drug molecule which would display highest solubility. We successfully demonstrated that there exists an optimized MSN pore size displaying highest aqueous solubility by studying pore size – solubility relationship for a given hydrophobic drug molecule.

In this research work, we further attempted to enhance the cytotoxicity of the hydrophobic anticancer drug using MSNs as carrier system. The most preferred strategy for targeting cancer cells and enhancing anticancer drug’s cytotoxicity is by designing the carrier system with positive surface charge. Positively charged carrier systems are reported to demonstrate high cellular uptake by cancer cells as cancer cells are negatively charged. However, bare positively charged carriers display toxicity, raising concern for its application.

To understand the parameters influencing the cellular uptake of MSNs in enhancing the anticancer drug’s cytotoxicity, we synthesized MSNs with different surface functionalities. Surface functionalization was performed on MSNs to study the effect of surface charge and hydrophobicity by encapsulating anticancer drug in the pores of MSNs. We found that, the negatively charged MSNs have faster drug release and low cellular uptake while positively charged MSNs showed relatively slower release and high cellular uptake. However, the anticancer activity displayed by negatively charged MSNs is similar to the positively charged MSNs. The similar anticancer activity could be attributed to the effect of cellular uptake and in vitro release. The hydrophobic MSNs did not enhance the anticancer activity owing to its hydrophobic surface leading to poor wetting effect.

These results were further confirmed by selecting another hydrophobic drug molecule which demonstrated enhancement in drug solubility and drug release by negatively charged MSNs compared to the positively charged MSNs and hydrophobic MSNs. The findings from this work hints towards a new approach in designing carrier system for cancer treatment. The research work in this thesis contributes to new strategies to achieve solubility enhancement for hydrophobic drugs and designing carrier system to enhance cytotoxicity of hydrophobic anticancer drugs promising their application in the pharmaceutical field.
Keyword Mesoporous silica nanoparticles
Pore size reduction
Drug delivery
Surface functionalization
Cell cycle
Cell apoptosis

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Created: Tue, 14 Oct 2014, 21:34:24 EST by Siddharth Jambhrunkar on behalf of Scholarly Communication and Digitisation Service