Novel intelligent pharmaceutical form fights against cancer
Researchers of the Institute of Chemical Technology (ITQ), a joint centre of the Polytechnic University of Valencia and the Spanish National Research Council, presented recently at the 5th FEZA Conference the latest scientific achievements in the development of novel intelligent pharmaceutical forms, based in mesoporous silica nanoparticles, for their application in cancer treatment.
This novel therapeutic platform is made of small mesoporous silica nanoparticles, in the range of nanometers, which surface is functionalized with organic groups, thus giving an organic-inorganic hybrid material. In addition, the drug (camptothecin) is linked to such organic groups through a chemical bond sensitive to intracellular enzymes. This system enables drug and mesoporous material to enter the body and selectively accumulate in tumor cells by means of a enhanced permeability retention (EPR) mechanism. Within the cell, the activity of specific enzymes (carboxylases) allows for controlled and continuous release of camptothecin, provoking cell death by means of a topoisomerase-I inhibition mechanism. In this way, higher efficiency than in previous therapy is ensured (based in structural derivatives of camptothecin, less active and with very short plasma clearance time), as well as total lack of secondary effects in other tissues due to the cytotoxic activity of camptothecin.
Currently, ITQ researchers are using this novel system at the lab scale on mice (human colorectal xenografts) and the results achieved, recently published in the Journal of Controlled Release, are very promising.
According to Pablo Botella, Tenured Scientist of the ITQ, “we are at the preclinical stage, working in collaboration with the CIBBIM-Nanomedicine group of Hospital Vall d’Hebron, in Barcelona”. In this sense, “it is imperative to improve the biodistribution and the pharmacokinetics of the pharmaceutical form. Moreover, this must be tested in more animal models and different types of tumor before considering human testing. Actually, it is difficult to set a period before we can conduct clinical trials, as a mid-term study has not been carried out yet (current treatments in xenografts are usually performed during one to three months). Hence, we do not expect to move to the clinical stage in less than two years. The main problems of administering nanoparticulated vehicles in the living bod are the poor biodistribution, basically due to severe hepatic accumulation, and the lack of long-term studies that confirm the non-toxic character of nanoparticles. However, the improvedstability of the pharmaceutical preparation in biological fluids, the introduction of targeting molecules to cancer cells and the development of toxicological studies showing lack of toxicity of materials, together with the complete elimination from the body after treatment will introduce a new generation of intelligent drugs able to perform their therapeutic activity with no secondary effects”.
Figure: Antitumor activity of silica-camptothecin nano-hybrids (SNP-CPT)
The first scheme shows the hybrid nature of the pharmaceutical form, with a nucleous made of silica nanoparticles and an organic shell containing the therapeutic agent. The second image shows growth evolution of tumor HT-29.Fluc in athymic female mice (day 22 of treatment) by bioluminescence image. Left: the control was administered saline solution. Right: mouse received two injections per week of a SNP-CPT suspension in saline solution, corresponding to a 0.8 mg CPT/kg dose. Significant tumor recession and necrosis in the SNP-CPT treated mouse can be observed.
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