Current chemotherapeutic regimens involve the administration of a combination of agents with hopes of gaining synergistic cell-killing effects observed in vitro . However, drug synergy is rarely realized clinically given the different pharmacokinetic profiles of the drugs. Recent findings show that a combination of rapamycin and paclitaxel proves highly effective at hindering growth of tumors wherein the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. Our objective was to fabricate a micellar nanotherapeutic platform capable of delivering a multitude of agents shown to synergistically affect a specific pathway (PI3K/Akt/mTOR) in breast cancer. We hypothesized that this concomitant delivery strategy will result in increased antitumor efficacy, given the site-specific and controlled delivery of the two agents. Herein, we demonstrate the successful fabrication of a nanotherepeutic strategy for the treatment of breast tumors with aberrant PI3K/Akt/mTOR pathways. Resulting polymer micelles were small in size (∼30 nm) and showed high levels of drug incorporation efficiency of both rapamycin and paclitaxel. Current studies involve the examination of release kinetics and antitumor efficacy in in vitro and in vivo models.

Our research group was the first one to microfabricate and demonstrate nano-channels in silicon membranes (1, 2). We employed nano-channeled chips to provide immuno-isolation for cell transplantation towards the treatment of diabetes (3), for biomolecular separation (4), and for the controlled passive and active release of drug molecules from implanted capsules (5). We showed that the constraints placed upon molecular agitation in nano-channels affected their concentration-driven transport kinetics (6, 7). A zero-order passive release of biological molecules was achieved, by the rational tailoring of nano-channels dimensions. This achievement allowed releasing of a constant amount of drugs over a long period of time. However, the development and optimization of many drug therapies require long-term drug delivery with controlled but variable dosage using miniaturized systems (8). Moreover, application such as drug release from implanted devices requires tight operational control, of regulatory agency caliber. We have engaged in the development and characterization of elecroosmotic nano-channels membranes, and present our results in this communication. These include the influence of the drug release rate on nanochannel size, membrane configuration, and applied voltage.

A multistage delivery system based on biodegradable mesoporous silicon particles loaded with one or multiple second stage nano-particles is likely to be useful for drug delivery. Upon intravenous injection the silicon nano-carriers will travel through the blood stream and migrate to the vessel wall. Vascular endothelial cells have been shown to be promising candidates for drug delivery as they represent both an anchor point and target.[1] It has been shown that human endothelial cells can act as nonprofessional phagocytes internalizing our silicon micron-sized nano-carriers.[2] The complete understanding of the molecular mechanisms required for the internalization of the particles into cells, as well as their fate once internalized, is crucial for the choice and formulation of appropriate second stage particles to be loaded in the silicon carrier. For example, different types of coatings or functionalization for both silicon nano-carriers and nano-particles could favor different trafficking pathways or promote endosomal escape following cellular uptake. In this study the uptake and trafficking of silicon nano-carriers in Human Microvascular Vein Endothelia Cells (HMVECs) was monitored using TEM, confocal microscopy and immunofluorescence.

The interface of silica nanochannel of 10 nm was studied by molecular modeling and experimental methods. Molecular Dynamics study on glucose solution revealed that 2–3 nm of interface solution to silica walls has reduced glucose diffusivity. That reduction affects the effective diffusivity of glucose in silica nanochannel. Experimental results show Fickian-like release of glucose through 13 nm nanochannel. Molecular modeling and experimental results suggest that glucose is not sufficiently confined to possess non-Fickian behavior.

The rapid advancement of silicon fabrication techniques has enabled the production of large numbers of precisely designed devices. Such devices are appealing to a wide range of industries and have already seen use in energy conversion [1] and medical applications [2]. Our group’s interest is in the latter; specifically the use of micro- and nanofabricated channels in silicon for the controlled release of drugs.