Victor Shang-Yi Lin

Bioanalytical, Bioinorganic, & Materials Chemistry.


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Research Interests

A long-term research goal in our group is to develop chemical methods for the synthesis of multifunctionalized mesoporous materials for applications in biotechnology and catalysis areas. To realize this goal, we have designed novel strategies to control the porous structure, particle morphology, biocompatibility, and degree of functionalization of these materials. We have demonstrated that the multifunctionalized mesoporous silica nanoparticle (MSN) materials prepared by our strategies exhibit promising potential in several emerging research fields, such as controlled release drug delivery, gene transfection, non-invasive neurotransmitter sensor design, and selective catalysis as outlined below.

(1) Tuning the Degree of Organic Functionalization and Particle Morphology of Mesoporous Silica Nanoparticle Materials via an Interfacially Designed Co-condensation Method

We have recently developed a synthetic approach that allows efficient multi-functionalization with precise control of the relative concentrations of functional moieties. Furthermore, our method provides means to modify the particle and pore morphology.

As depicted in Figure 1, our method involves the utilization of organotrialkoxysilanes with various anionic, hydrophobic, or hydrophilic functional groups that could provide different noncovalent interactions, e.g., electrostatic attractions, hydrophobic interactions, etc., with the cationic cetyltrimethylammonium bromide (CTAB) surfactant micelles in a base-catalyzed condensation reaction of tetraethoxysilane (TEOS). By carefully designing the interfacial interaction between the surfactant head groups and the desired organic functional group precursors, we have reported that the extent of organic functionalization as well as the particle shape and size of MSNs can be controlled and fine-tuned. As shown in Figure 2, a series of organically functionalized MSN materials with spherical, tubular, and rod-like particle morphologies and narrow particle size distributions could be easily synthesized via our designed method.

(2) Capped Mesoporous Silica Nanospheres as Controlled Release Drug Delivery and Gene Transfection Carriers

Amorphous mesoporous silicas synthesized by the conventional procedures typically show very poor biocompatibility with various cell cultures. In particular, the cell growth and differentiation processes of mammalian cells were shown to be rapidly hindered and eliminated upon introduction of organo-functionalized mesoporous silicas synthesized by conventional methods.

Unlike the amorphous mesoporous silicas, our monodisperse, organically functionalized MSN materials are highly biocompatible. By using these biocompatible MSNs as carriers, we have designed a stimuli responsive, controlled release drug delivery system. In contrast to many current polymer-based delivery systems, the molecules of interest were encapsulated inside the porous framework of the MSN not by adsorption or sol-gel types of entrapment, but by covalently capping the openings of the mesoporous channels with size-defined “caps”, such as dendrimers, proteins, and semiconductor nanocrystals (quantum dots), to physically block the drugs from leaching out (Figure 3). Drug molecules loaded into the pores were released by the introduction of “uncapping triggers” (molecules that can cleave the chemical linkers connecting the caps to the mesoporous surface). The rate of release was controlled by the concentration of the trigger molecules. Prior to uncapping, the capped MSN system exhibited negligible release of drug molecules. This “zero release” feature along with the ability to tune the rate of release by varying stimulant concentrations are important prerequisites for developing delivery systems for many site-specific applications, such as delivery of highly toxic anti-tumor drugs, hormones, and neurotransmitters to certain cell types and tissues.

Also, we have developed an MSN-based gene transfection system, where second generation (G2) polyamidoamine (PAMAM) dendrimers were covalently attached to the surface of MSN. The G2-PAMAM-capped MSN material (G2-MSN) was used to complex with a plasmid DNA (pEGFP-C1) that codes for an enhanced green fluorescence protein (GFP) as depicted in Figure 4. The system showed high gene transfection efficiencies of GFP in many different cell types, such as neural glia (astrocytes), human cervical cancer (HeLa), and Chinese hamster ovarian (CHO) cells. We have reported that the high transfection efficiency of this system was due to the direct endocytosis of the G2-PAMAM-capped MSNs by these mammalian cells. This discovery renders the possibility of using such a system as a universal transmembrane carrier for intracellular drug delivery and imaging applications by encapsulating membrane impermeable molecules, such as pharmaceutical drugs and fluorescent dyes, inside the MSN channels.

(3) Multifunctionalized Mesoporous Silica Nanosphere-based Fluorescence Probes for Non-invasive Detection of Neurotransmitters

Recent stem cell therapy, where stem cell cultures are implanted into patients' brains to replace damaged neurons, suffers from “outgrowth” problems, i.e., some of the stem cells differentiate into other cell types, such as muscle cells and tumor cells. One of our research goals is to design a “non-invasive” probe to identify dopamine-releasing neurons (DA-neurons) from adult or embryonic stem cell cultures. This approach will allow the isolation of an enriched population of DA-neurons for clinical transplantation and therapeutic treatment of neuronal diseases, such as Parkinson's disease, to circumvent the outgrowth problem. Current neural cell-function marking/detection methods are “invasive” in nature. The damage caused by these analytical methods to the analyzed cells prevents the further utilization of these function-marked cells in transplantation and other clinical applications.

To overcome this “catch-22” situation, we have developed a series of organically functionalized mesoporous silica materials that can serve as fluorescence probes to selectively identify DA-neurons in vitro without harming them. As illustrated in Figure 5, we selectively functionalized the interior mesopore surface of MSN with an amine sensitive functional group (OPTA) that can react with neurotransmitters with primary amine groups and form the corresponding fluorescent isoindole products. The exterior surface of the OPTA-MSN was then coated with a poly(lactic acid) (PLA) layer. We have reported that the system can selectively detect dopamine from other structurally similar neurotransmitters, such as tyrosine, and glutamic acid in pH 7.4 PBS buffer. The isoelectric points (pI's) of dopamine, tyrosine, and glutamic acid are 9.7, 5.7, and 3.2, respectively, whereas the pI of PLA is typically below 2.0, which means the dopamine would be positively charged and the others will be negatively charged under physiological condition (pH 7.4). The different electrostatic interactions between these neurotransmitters and the PLA layer of our sensor system allow us to use the PLA layer as a “gatekeeper” to regulate the rates of diffusion of the amino acid-based neurotransmitters into the mesopores of the MSN. We envision that this multi-functionalized MSN material could serve as a non-invasive probe in a flow cytometry system to identify dopaminergic neurons in stem cell cultures.

Multifunctionalized Mesoporous Silica Nanospheres for Selective Catalysis

Many researchers have taken advantage of the high surface area of mesoporous silicas as solid supports for their high catalytic activity. In contrast to using mesoporous silicas simply as an inert support with high surface area, we intend to exploit its unique porous structure as a new 3-D scaffold that, in a way, mimicks the underlying design principle of enzyme active sites. Through multifunctionalization of the mesoporous surface in order to control and tune the density, spatial location/orientation of a variety of moieties, we aim to construct a new generation of catalysts whose selectivity and reactivity are dictated by a series of covalent and non-covalent interactions between the reactants and all the functionalities in the pores, and not by the particular structure of one catalytic group as shown in Figure 6.

To this end, we have developed a synthetic strategy that offers the ability to tune the relative ratio of different functional groups without altering the pore and particle morphology of the mesoporous silica. By introducing two organoalkoxysilanes as precursors in our co-condensation reaction, we can utilize one precursor with stronger structure-directing ability to create the desired pore and particle morphology and employ the other for selective immobilization of catalysts. This strategy allows us to generate a series of multi-functionalized mesoporous silicas with control of both morphology and degree of functionalization. As a proof of principle, we have synthesized and reported a series of bifunctionalized MSN-based heterogeneous catalysts for nitroaldol (Henry) reaction. As shown in Figure 6, a common 3-[2-(2-aminoethylamino)ethylamino]propyl (AEP) primary group and three different secondary groups, ureidopropyl (UDP), mercaptopropyl (MP), and allyl (AL) functionalities, were incorporated into these mesoporous silica materials by introducing equal amounts of AEP-trimethoxysilane with UDP-, MP- or AL-trialkoxysilane precursors to the aforementioned co-condensation reaction. The AEP group served as a catalyst and the other secondary groups provided different non-covalent interactions to reactants and thereby controlled the reaction selectivity. By varying the secondary group in these bifunctionalized MSN catalysts, we discovered that the selectivity of a nitroaldol reaction of two competing benzaldehydes reacting with nitromethane could be systematically tuned simply by varying the physicochemical properties of the pore surface-bound secondary groups, i.e. polarity and hydrophobicity (Figure 7).