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First Workshop on Nanomedicine for Infectious Diseases of Poverty, 2731 March 2011, Magaliesberg, South Africa

May/June 2011

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Aptamers in Nanomedicine

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).

Other Subjects Covered by the Workshop

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.

Meeting Summary

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.

Of note, several recent reviews have summarised research over the last 15 years into nanoformualations of antiretrovirals.21,22 See Figure 4.

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.

Figure 4: Examples of Antiretroviral Formulations With Improved Pharmacokinetics

ARV Process Aim/Target Study Model Effect References

(also d4T, delavirdine, saquinavir)

Multiple polymers and solid lipids. Aim to cross blood brain barrier by endocytosis and/or phagocytosis to release drug intracellularly. In vivo (cell) i.e. permeability of AZT increased 8-20 fold and 3TC by 10-18-fold with PBCA. 100% increase across BBB. Kuo et al.
Int J Pharm 2005, 2006, 2007, 2008.
lopinavir Emulsion templated, freeze-dried nanoparticle dispersions Improve PK, develop PI formulation that doesn't need ritonavir boosting. In vivo (cell) Increased cellular uptake vs aqueous fomulation. Smith D et al. CROI 2011.
d4T, AZT, 3TC, efavirenz Spray dried PCL nanoparticles. Improve PK, reduce dosing time and toxicity. Mouse Sustained release reducing dosing. CSIR, South Africa
saquinavir Nanoparticles with PEG and gene delivery Increase PK, controlled release in mucosal tissue In vivo Large particles (200-500 nm) able to overcome challenge of mucosal PK. Lai et al.
Adv Drug Deliv Rev 2009.
Ritonavir, lopinavir, efavirenz, indinavir Added to poly-caprolactone polymer in methylene chloride (multiple emulsion solvent) Improve PK, reduce dosing time and toxicity.

Cross blood-brain barrier and macrophage uptake.

In vitro Drug detected after 28 days in PBMCs vs <2 days with unencapsulated formulation. Destache et. CROI 2008.
BMC Infect Dis, 2009.
CCR5 inhibitor (TAK-779) Gold nanoparticles as a base scaffold. Restore activity of an inactive CCR5 inhibitor. In vitro Proof of principal for drug delivery. Bowman et al. CROI 2008.
AZT PLA and PLA-PEG blend particles Increased uptake by phagocytes. In vitro Improved phagocyte uptake with PLA. Mainardes et al.
J Pharm Sci 2009.
3TC, efavirenz Tuftsin dendrimers Target macrophages, prolong half-life In vitro Cellular uptake >20-fold higher vs free drug, prolonged release >140 hours, increased ARV potency at lower concentrations. Dutta et al.

Biophys Acta 2007
Eu J Pharma Sci 2008

Compiled from Malipeddi and Rohan21, Govender23 and others.

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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.
See Also
More on HIV Medications
HIV Drugs in Development

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