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खुला एक्सेस

अमूर्त

Has the Time for In silico Design of Nanomedicines Finally Arrived?

Igor F. Tsigelny and Dmitri Simberg

Cancer therapy and diagnostics are among the most appealing and well-studied applications of nanomedicine (a recent PubMed query of "nanoparticle delivery+ tumor" returned over 2,400 hits). Targeted drug delivery is based on the notion that nanoparticles (NPs) could be designed to overcome chemotherapy's systemic toxicity by specifically penetrating tumor tissue and delivering drugs directly to the cancer cells. The delivery of medications to a majority of cells at the primaryand metastatic sites is of critical importance to the success of such chemotherapeutics. However, as noted recently by Bae and Park in their excellent recent perspective in the Journal of Controlled Release [1], efficieint delivery of these drugs to tumors has yet to be achieved. The authors provide multiple reasons for the lack of success of targeted NPs, including: 1. Tumor heterogeneity; 2. Tumor penetration and diffusion problems; 3. An insufficient number of targetable cell receptors; 4. Unfavorable nanoparticle pharmacokinetics, where >95% of the injected dose is wasted due to NP uptake by immune organs. How are we to solve these apparently challenging problems? One potential approach is that of the Ruoslahti and Tuveson groups, which recently used Hedgehog inhibitors [2] and Neuropilin-1 agonists [3] to improve tumor penetration by exploiting biological mechanisms. These strategies resulted in a remarkable enhancement of tumor penetration by NPs and drugs. Similarly, cancer genomics and proteomics provide enormous amounts of information on tumor markers and receptors, which could be exploited for targeting multiple populations inside the tumor, including tumor macrophages, stromal cells, and stem cells. Significant progress has been made in understanding the interactions of NPs with the biological milieu and the effect of these interactions on the clearance of nanoparticulates.