First Workshop on Nanomedicine for Infectious Diseases of Poverty, 2731 March 2011, Magaliesberg, South Africa
Dr Makobetsa Khati, also based at the CSIR explained the utility of nanoaptamer biconjugates against infectious diseases with a focus on HIV.19
DNA or RNA aptamers were first developed in 1990 and are usually short strands of artifical oligonucleotides that are selected in vitro using SELEX (systematic evolution of ligands by experimental enrichment).
At a size that is less than 10 nm radius they can increase tissue specificity with minimal impact on the size of the formulation. Current uses include delivery of drugs to treat age related macula degeneration. Aptamers have the molecular recognition properties of monoclonal antibodies in terms of their high affinity and specificity. They are chemically simple, easy to make, have high target specificity, are non-toxic and non-immunogenic. Aptamers are used in many of the formulations already discussed in order to identify target cells for nanoformulations.
As aptamers can block entry this group has worked with oligonucleotides that are active against gp120.15 The aptamer doesn't affect cell metabolism with toxicity, immune of cardiovascular cells. Over 80% of cells were sensitive with IC50 <1 nm and non-toxic at concentrations over 1000 nm.
In humanised mice Neff and colleagues showed reduction in viral load and a protective effect on CD4 counts with either the anti-gp120 aptamer or an aptamer-siRNA combination (that provided more extensive inhibition, resulting in a significantly longer antiviral effect that extended several weeks beyond the last injected dose).20
In the discussion after the presentation it was noted that the loss of the patent for the one aptamer on the market has dramatically reduced the cost (from $100,000 down to $25 per mg. However, as they are highly negatively charged this raised the issue of pharmacokinetics and side effects (clotting, platelets and immune effects).
The workshop explored a wide range of other potential indications for nanomedicines that are not covered in this report including pulmonary fungal and parasite infections (including paracoccidioides brasiliensis), tuberculosis, malaria and prostate cancer.
It also included sessions on regulatory issues (with reference to the recent first meeting of the EMA on nanotechnology) and practical aspects of intellectual property, patents, technology transfer and international research collaborations.
Many aspects of these new technologies are still in early development, even though some nanoparticle medicines have been used so extensively used that they are now off-patent. Each molecule has specific efficacy and safety issues dependent on the particular manufacturing process and cellular target.
Antiretroviral compounds show exciting pharmacological properties in in vitro studies. Particularly greater potency and that they require lower quantities of the API. The benefits from suspension formulations in development from researchers on nevirapine in South Africa and efavirenz in Argentina could have global impact as paediatric formulations. However, they still need to show proof of concept for overcoming obstacle associated with lymphocyte target cells.
The potential for TB nanoformulations may be closer than those active against HIV. The CSIR researchers have nanoparticle formulations of the four main first-line TB drugs and are working with the TB Alliance on newer compounds including TMC 207.
Some issues from a regulatory safety perspective are still not resolved . The FDA is more advanced than the EMA. Nearly all research is preclinical, with animal or in vitro data to support advantages of nanformulations. Particles based on molecules with established safety data should be easier to assess than totally new constructs. But one of the discussions on regulation of generic formulations of Doxil indicated that the complexity of the manufacturing process is likely to require in vivo safety and efficacy data from new studies in every molecule rather than just bioequivalence studies that enabled easier widespread use of oral antiretrovirals.
It is also important to balance expectations with likely realities for this research. Nanoformulations look as if they will offer exciting solutions to some specific currently unmet challenges rather than the potential to revolutionise treatment for every disease indication. Specific targeting of malignant tissue and its supportive vascular structures is revolutionising approaches to treatment of some cancers.
The political aspect of the workshop included the importance of technology being developed in countries where the demand for final medicines exists. With broadly 10% of global research focused on the 90% of global medical need. Less than 2% of patents are held in Africa and intellectual property and patent legislation are determined to benefit companies based in the developed world.
This research is generally conducted by small independent groups working without sufficient funding to discover whether the potential of this technology can be realised for HIV care.
Given the potential advantage of providing reduced toxicity, more durable formulations with improved pharmacokinetics (ie targeting macrophages to increase concentrations in lymph tissue and dramatically extending half-life and dosing intervals) and at a reduced cost makes it frustrating that so far none of these formulations has yet progressed to human studies.
This article was provided by HIV i-Base. It is a part of the publication HIV Treatment Bulletin. Visit HIV i-Base's website to find out more about their activities, publications and services.
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