|Faculty: Mauro Ferrari, Ph.D., Biana Godin-Vilentchouk, Ph.D., Rita Serda, Ph.D., Haifa Shen, Ph.D., Ennio Tasciotti, Ph.D., Jason Sakamoto, Ph.D., Arturas Ziemys, Ph.D.|
Problem: An abundance of barriers reduce the likelihood that drugs and imaging agents will reach the site of action. For drugs delivered by intravenous injection, these include enzymatic degradation, uptake by the reticulo-endothelial system and crossing the endothelial barrier, cellular membranes, and cellular efflux pumps.
Despite extraordinary progress in the research laboratory, cancer mortality has not been reduced significantly in the last fifty years. There is a need to achieve an efficient concentration of the drug in the target tissue with minimal distribution in healthy tissue. Overcoming these biological barriers, delivering one or multiple entities, and personalizing therapy have historically been addressed by trying to endow individual drug molecules with one or all of these capabilities.
|Schematic summary of possible MSV mechanisms of action. Central compartment: hemispherical or disc-shaped nanoporous silicon S1MPs are engineered to exhibit an enhanced ability to marginate within blood vessels and adhere to disease-associated endothelium. Once positioned at the disease site, the S1MP can (top right) release the drug/siRNA-loaded S2NP to achieve the desired therapeutic effect, prior to the complete biodegradation of the carrier particle; release an imaging agent (top left) or external energy-activated S2NP (e.g., gold nanoparticles, nanoshells, bottom right). Another possible mechanism of action is cell-based delivery of the MSVs into the disease loci followed by triggered release of the S1MP/S2NP from the cells (bottom left) .|
Approach: Nanotechnology offers unprecedented opportunities to develop treatments that increase therapeutic efficacy, decrease undesired side effects, and effectively achieve the personalization of intervention for conditions such as cancer and cardiovascular and infectious diseases. The majority of current nanotherapeutics/nanodiagnostics in clinics and under investigation accommodate single- or multiple functionalities on the same entity. However, due to a multiplicity of heterogeneous biological barriers, therapeutic and imaging agents are unable to reach their intended targets in sufficient concentrations. Thus we envisioned and introduced a Multi-Stage nanoVector in which different nanocomponents (or stages) responsible for a variety of functions are decoupled but act in a synergistic manner [1, 2]. Stage 1 Mesoporous silicon Particles (S1MP) were rationally designed and fabricated using semiconductor fabrication techniques, photolithography and electrochemical etching , in a non-spherical geometry to enable superior blood margination and to increase cell surface adhesion. S1MP can be chemically modified with negatively/positively charged groups , polymers , fluorescent probes , and biologically active targeting moieties . The main task of S1MP is to efficiently transport the payload nanoparticles, termed Stage 2 NanoParticles (S2NP), which are loaded into the porous structure. Depending upon the S1MP surface modifications and porosity, a variety of S2NPs (such as liposomes, micelles, metal particles, and carbon structures) or nanoparticle “cocktails” can be loaded and efficiently delivered to the disease site, enabling simultaneous functions. The versatility of the MSV platform allows for a multiplicity of applications. In MSV, novel properties emerge, enabling the design of new generations of imaging contrast agents and therapeutics. For example, loading of contrast agents for magnetic resonance imaging to hemispherical and discoidal S1MP enabled a significant increase in contrast efficiency (up to 50 times compared to clinically available agents) . Furthermore, administration of a single dose of MSV loaded with nanoliposomes containing siRNA enabled sustained gene silencing for at least 21 days and, as a result, reduced tumor burden in orthotopic ovarian cancer mouse models . We have also shown that intracellular trafficking and cell-to-cell communication can be controlled by surface modifications of S1MP and S2NP. The therapeutic and imaging potential of MSV is being investigated in primary and disseminated tumors as well as in cardiovascular and infectious diseases.
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