Multifunctional Mesoporous Silica Nanoparticles for Cancer-Targeted and Controlled Drug Delivery

Proteins that contain the Arg-Gly-Asp (RGD) attachment site, together with the integrins that serve as receptors for them, constitute a major recognition system for cell adhesion. The RGD sequence is the cell attachment site of a large number of adhesive extracellular matrix, blood, and cell surface proteins, and nearly half of the over 20 known integrins recognize this sequence in their adhesion protein ligands. Some other integrins bind to related sequences in their ligands. The integrin-binding activity of adhesion proteins can be reproduced by short synthetic peptides containing the RGD sequence. Such peptides promote cell adhesion when insolubilized onto a surface, and inhibit it when presented to cells in solution. Reagents that bind selectively to only one or a few of the RGD-directed integrins can be designed by cyclizing peptides with selected sequences around the RGD and by synthesizing RGD mimics. As the integrin-mediated cell attachment influences and regulates cell migration, growth, differentiation, and apoptosis, the RGD peptides and mimics can be used to probe integrin functions in various biological systems. Drug design based on the RGD structure may provide new treatments for diseases such as thrombosis, osteoporosis, and cancer.

Surface-functionalized silica nanoparticles can deliver DNA and drugs into animal cells and tissues. However, their use in plants is limited by the cell wall present in plant cells. Here we show a honeycomb mesoporous silica nanoparticle (MSN) system with 3-nm pores that can transport DNA and chemicals into isolated plant cells and intact leaves. We loaded the MSN with the gene and its chemical inducer and capped the ends with gold nanoparticles to keep the molecules from leaching out. Uncapping the gold nanoparticles released the chemicals and triggered gene expression in the plants under controlled-release conditions. Further developments such as pore enlargement and multifunctionalization of these MSNs may offer new possibilities in target-specific delivery of proteins, nucleotides and chemicals in plant biotechnology.

The folate receptor is a highly selective tumor marker overexpressed in greater than 90% of ovarian carcinomas. Two general strategies have been developed for the targeted delivery of drugs to folate receptor-positive tumor cells: by coupling to a monoclonal antibody against the receptor and by coupling to a high affinity ligand, folic acid. First, antibodies against the folate receptor, including their fragments and derivatives, have been evaluated for tumor imaging and immunotherapy clinically and have shown significant targeting efficacy in ovarian cancer patients. Folic acid, a high affinity ligand of the folate receptor, retains its receptor binding properties when derivatized via its gamma-carboxyl. Folate conjugation, therefore, presents an alternative method of targeting the folate receptor. This second strategy has been successfully applied in vitro for the receptor-specific delivery of protein toxins, anti-T-cell receptor antibodies, interleukin-2, chemotherapy agents, gamma-emitting radiopharmaceuticals, magnetic resonance imaging contrast agents, liposomal drug carriers, and gene transfer vectors. Low molecular weight radiopharmaceuticals based on folate conjugates showed much more favorable pharmacokinetic properties than radiolabeled antibodies and greater tumor selectivity in folate receptor-positive animal tumor models. The small size, convenient availability, simple conjugation chemistry, and presumed lack of immunogenicity of folic acid make it an ideal ligand for targeted delivery to tumors.