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Seeking New Chemocatalytic and Biocatalytic Solutions
Advances in palladium-catalysed hydrogenation, visible-light photocatalysis and improved chemocatalytic approaches for making heterocyclic compounds are some recent industry developments.

Pharmaceutical Technology Europe

Formulation development forum: targeted polymeric nanoparticles

Researchers recently reported positive clinical results for a targeted therapeutic nanoparticle as an anticancer therapy. The targeted nanotechnology-based, drugdelivery method is considered an important breakthrough in targeting and better controlling dosing of a chemotherapeutic agent.

The targeted polymeric nanoparticle (TNP) contained the chemotherapeutic docetaxel and was developed from a combinatorial library of more than 100 TNP formulations varying with respect to particle size, targeting ligand density, surface hydrophilicity, drug loading and drug-release properties (1). The targeted nanoparticle, BIND-014 is a nanomedicine that combines a targeting ligand and a therapeutic nanoparticle containing docetaxel encapsulated in biocompatible and biodegradable polymers. BIND-014 is targeted to the prostatespecific membrane antigen (PSMA), a cellsurface antigen abundantly expressed on the surface of cancer cells and on new blood vessels that feed a wide array of solid tumours. In preclinical cancer models, BIND014 was shown to deliver tenfold more docetaxel to tumours than an equivalent dose of conventional docetaxel. The increased accumulation of docetaxel at the site of disease translated to marked improvements in antitumour activity and tolerability, according to an April press release from the Prostate Cancer Foundation.

BIND-014 entered trials in January 2011. Phase I clinical trial was performed by researchers at the biopharmaceutical company BIND Biosciences, a company cofounded by Robert Langer, the David H. Koch Institute Professor in the Department of Chemical Engineering at the Massachusetts Institute of Technology (MIT) and Omid Farokhzad, director of the Laboratory of Nanomedicine and Biomaterials at Brigham and Women's Hospital, associate professor of anesthesia at Harvard Medical School.

"The initial clinical results of tumour regression even at low doses of the drug validates our preclinical findings that actively targeted nanoparticles preferentially accumulate in tumours," said Langer, in a MIT press release. "Previous attempts to develop targeted nanoparticles have not successfully translated into human clinical studies because of the inherent difficulty of designing and scaling up a particle capable of targeting tumours, evading the immune system, and releasing drugs in a controlled way."

The BIND-014 nanoparticles have three components: one that carries the drug, one that targets PSMA and one that helps evade macrophages and other immune-system cells. "This study demonstrates for the first time that it is possible to generate medicines with both targeted and programmable properties that can concentrate the therapeutic effect directly at the site of disease, potentially revolutionising how complex diseases such as cancer are treated," said Farokhzad in the MIT release. One of the challenges in developing effective drug-delivery nanoparticles is designing them so they can evade the body's normal immune response and reach their intended targets. "You need exactly the right combination of these properties because if they don't have the right concentration of targeting molecules, they won't get to the cells you want, and if they don't have the right stealth properties, they'll get taken up by macrophages," added Langer.

The Phase I clinical trial involved 17 patients with advanced or metastatic tumours who had already gone through traditional chemotherapy. To determine safe dosages, patients were given escalating doses of the nanoparticles. In the 48 hours after treatment, the researchers found that docetaxel concentration in the patients' blood was 100 times higher with the nanoparticles as compared to docetaxel administered in its conventional form. Higher blood concentration of BIND-014 facilitated tumour targeting resulting in tumour shrinkage in patients, in some cases with doses of BIND-014 that correspond to as low as 20% of the amount of docetaxel normally given. The nanoparticles were also effective in cancers in which docetaxel usually has little activity,. The researchers also found that in animals treated with the nanoparticles, the concentration of docetaxel in the tumours was up to tenfold higher than in animals treated with conventional docetaxel injection for the first 24 hours, and that nanoparticle treatment resulted in enhanced tumour reduction.

The Phase I clinical trial is still ongoing. BIND Biosciences is now planning Phase II trials, which will further investigate the treatment's effectiveness in a larger number of patients.


1. R. Langer et al., Sci. Transl. Med. 4 (128), 39 (2012).


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