Nanoparticle-mediated enzyme delivery for application in cancer therapy
Posted: 9 March 2017 | Mukanth Vaidyanathan (University of California), Negin Mokhtari (University of California), Sadik Esener (University of California), Ya-San Yeh (University of California) | No comments yet
Enzyme therapy is a promising form of cancer treatment. The specific nature of enzyme and substrate interaction gives enzyme therapy an edge compared to standard non-specific therapies such as radiation and chemotherapy. However, since most of these enzymes are of a foreign nature, the delivery of these immunogenic enzymes has been a challenge. This study shows that enzyme encapsulation in nanoparticles may shield them from the immune system, allowing for the potential of targeted delivery and reduction of off-target adverse side effects.
In 2012, 14.1 million patients were diagnosed with cancer, of which 8.2 million cases were fatal. This number is expected to rise to 19.3 million new cancer cases by 2025.1 There are several therapy techniques available to treat cancer, but with limited success. Chemotherapy (either single or in combination), surgery and radiation therapy have not been successful in improving the survival of patients, despite tumour response having been favourable.2,3 Success rates of 15-20% have been observed with immunotherapy. Even with these advanced treatments available commercially, newer methods are still required to improve the survival and quality of life of the patient. One effective method for the treatment of cancer is amino acid depletion therapy.
Asparaginase and arginine deaminase lower non-essential amino acid asparagine and arginine, respectively, in circulation. Asparaginase is effective for the treatment of acute lymphoblastic leukaemia,4 and arginine deaminase for treating melanoma and hepatocellular carcinoma.5 Hence, there is a priority in amino acid depletion therapy for the treatment of cancer. Moreover, many of the potent cancer drugs are also toxic to normal cells. To overcome the systemic toxicity of cancer drugs, a non-toxic pro-drug form of the potent drug can be activated with an enzyme at the tumour site.6 Unfortunately, most of these enzymes have a non-human origin, which generates immense antibody neutralisation and rapid clearance from the body.5
Currently there are two approaches to prevent an immune response against foreign enzymes and maintain the enzyme activity. First, the enzyme is modified directly, for instance with polyethylene glycol (PEG), which may cause partial loss of enzymatic activity and stability and in some cases generate immune response against PEG.7 As a result, enzyme modifications are met with limited success of protecting the enzyme from immune clearance. Second, is thorough encapsulation of modified or unmodified enzyme by organic/inorganic nanoparticles.8 The second method promises low-cost production and increased homogeneity.9