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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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Review of Nanomedicine

The conference opened with a plenary lecture from Professor Ruth Duncan from Cardiff University, who has been a leading researcher for over 35 years in community-based research (Cancer UK), industry and academia. This talk emphasised the diversity of expertise needed from different fields including pharmacology, chemistry, medicine, ethics, health policy and politics.

Material science has been reducing the size of everything. Nanotechnology has been a rapidly evolving field that includes a top-down approach (where compounds are reduced) and a bottom-up approach (assembling polymer materials from the bottom up). Advanced drug delivery systems have been the focus of research for over 40 years. Nanomedicines can prolong action using new control/release technology, can target specific organs, cells, or organ space in an organelle, and improve bioavailability, including penetration of the blood-brain barrier.

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Systemic distribution of most drugs involves a high level of dilution throughout the body and low concentrations at the active target. Nano-sized particles have different pharmacokinetics, delivering drugs by endocytosis and phagocytosis (cell engulfment) rather than passing directly through a cell wall. In addition to advancing drug delivery some nanoparticles are active in their own right. There are multiple targets through the lifecycle of infection and progression, including latent infection, each using different strategies.

The definition of nanomedicine incorporates engineering tools used outside the patient, biomedical and medical materials, imaging, and drug delivery and formulation. Designing nanomedicine should be easy. Starting with a target disease and product profile it should be possible to choose technologies and benchmark these against current treatment, with a clear stop-go development. Good lead candidates then require five years preclinical trials before getting to human studies. These drugs need a constant awareness of good laboratory practice (GLP), good manufacturing practice (GMP), good clinical practice (GCP) and ethics.

While nanomedicine has an unprecedented opportunity for invention, the lack of current knowledge across the field risks newer researchers repeating mistakes that earlier research has overcome. Against this is a caution that over exaggeration of the benefits will raise unrealistic expectations. Professor Gordon highlighted a limitation from the commercial focus on the target, using genomics and low molecular weight compounds, where 95% of compounds fail, probably because pharmacokinetics is not sufficiently important earlier in the development phase.

The first nanomedicines developed in the1990s based on liposome formulations are at the end of their patent life and are now coming through as generics. However each nanomedicine construct has a different design and route of delivery and every drug must be reviewed separately due to the specific challenges of manufacturing and constructing lipid-based nanoformulations. This field is more complex than generic antiretrovirals for example, where reproducing a compound that has similar pharmocokinetic properties is closely associated to similar safety and activity. From a safety perspective, producing new molecules, each piece (polymer, linker, etc) needs to be designed, requiring preclinical research before human studies. Many polymers for example are rejected for safety. Non-biodegradable polymers can accumulate, especially with long exposure (potentially lifelong) treatment. Pegylation itself covers a wide range of polymers. Currently the EMA opinion on generic formulations of Doxil etc is that bioequivilence does not exist for a liposome, only bio-similar properties and that pegylation on surface of liposome cannot just be duplicated as generic.

This complexity involves molecules travelling in the bloodstream at hundreds of miles an hour and the challenge is how to "stick your arm out to catch them at the right site". Shape and density are essential aspects of design including ionisation of polyelectrolytes and changes in cellular behaviours. Linkers need to be stable and release drug at the right time. Activating compounds can behave differently, including by sex. All of parts of the system will go somewhere and these need to be accounted for to ensure patient safety.

The importance of products used in clinical trials and subsequently approved to have passed good GLP and GMP was introduced as a theme that would be frequently revisited throughout the workshop.


Historical Perspective of Nanomedicines in Cancer Treatment

Dr Theresa Allen from the University of Alberta, Canada, and Alberto Gabezon from the Shaare Zedek Medical Center, Jerusalem gave lectures on the historical perspective of nanotechnology drawing on the impact that it has had on cancer therapy.

Although molecules on a nanoscale have been known since 1900 the term is associated with a lecture given by the Nobel physicist Richard Feynman in 1959 setting two challenges based on the theory that "atoms on a small scale behave like nothing on a large scale".

Nanotechnology based products already in common use include sunscreens (nanomolecules of titanium dioxide and zinc oxide are translucent, not white), self cleaning windows, pharmaceutical inks printing on medicines, and fabrics and coatings treated to variously repel dirt, water, bacteria, fungus or creasing.

In medicine, applications include imaging, diagnostics, drug delivery and therapeutic agents able to cross biological barriers. Nanomedicines deliver proteins, plasmid DNA, siRNA and antisense, enhanced permeability and retention (EPR) effect for solid tumours (where molecules target tissues with increased permeability and are only released in inflamed tissue and tumour damaged sites).

Nanomedicines can improve properties of existing drugs, reducing toxicity and improving bioavailability (poor bioavailability currently wastes an estimated 68 billion dollars annually).

Liposome and other lipid-based systems are the first and most common lipid medicines. They are simple, self-assembling, with proven safety, with flexibility in terms of particle size, release rates and bio distribution. A principal behind nanoformulations is that a drug changes its biological pharmacokinetics and distribution properties, generally being protected from degradation and metabolism, and only behaving as a regular molecule when released as free drug.

Examples of widely used nanomedicines include Doxil (a pegylated liposome encapsulation formulation of doxorubicin used to treat Kaposi's sarcoma [KS] and ovarian cancer), the antifungal AmBisome (a liposomal formulation of amphotericin-B) and pegylated interferon (used with ribavirin to treat hepatitis C), Abraxone (a nanoformulation of paclitaxil used to treat metastatic breast cancer), Rapamune (formulation of sirolimus that is milled down and stabilised to become soluble) and Genoxol PM (a micelle formulation of paclitaxil). See Figure 2.

Figure 2: Examples of Currently Approved Nanomedicines (Currently 18 in the EU)

Name Year Clinical Indication Comment
Doxil 1995 Kaposi's Sarcoma (KS)
Ovarian cancer
Pegylated liposome encapsulation formulation of doxorubicin
AmBisome 1997 Fungal infections, some antiprotazoal activity. Liposomal formulation of amphotericin-B
PegIntron and Pegasys 2001, 2002 Hepatitis C Pegylated interferons.
Abraxone 2005 Metastatic breast cancer Nanoformulation of paclitaxil.
Genoxol PM 1999 As paclitaxil: ovarian, KS, breast cancers. Micelle formulation of paclitaxil.
Rapamune 2000 Immunosuppressant to prevent organ graft rejection. Formulation of sirolimus that is milled down and stabilised to become soluble.

The first oncology nanomedicine was Doxil, approved in 1995 as a treatment for AIDS-related KS under fast track orphan drug designation with development time of less than ten years. Subsequent approvals for relapsed ovarian cancer, metastatic breast cancer and as a substitute for doxorubicin resulted in Doxil becoming a commercial 'blockbuster' drug.

Doxil is a 100 nm diameter surface-graft pegylated long-circulating formulation where the active drug stays in a liposome, increases the concentration in sold tumours and slow releases in tumour cells. If ligands are added to particles, the resulting package can enter a cell in larger quantities and where it is then released.

Compared to the original doxorubicin, Doxil dramatically reduced clearance by 1000-fold (extending the half-life to 50-70 hours) and increased drug accumulation in tumour tissue (approximately 80 ug vs 0.5 ug in skin a few millimetres away). This enabled a 4-fold lower dose of Doxil to have a 30% higher cure rate and reduction tumour volume. Unfortunately, in this early example, side effects were not always reduced and a higher rate of palmar-plantar erythema rash occured in some patients.

Nanomedicine can also incorporate combination chemotherapy in single constructs using drugs that use different mechanisms and that have non-overlapping side effects. It is possible to mix two liposomes or to add multiple targets on each (for example to target to nothing, CD20, CD19 or both and produce additive effects). In oncology, combination approaches to target and kill blood vessels in tumour tissue starve the tumour of oxygen and nutrients (though peripheral tumour cells survive). New blood vessels in a tumour are damaged, disorganised and with incomplete endothelial lining, allowing particles up to 400 nm to penetrate. An early paper in 1982 showed the potential of liposomes to carry adriamycin in mice. Conventional liposomes reduced cardiovascular risk but did not target liver tumours and were leaking drug in blood. Changing the lipid concentrations in new formulations changed pharmacokinetics with a 20-fold increase in concentrations in the tumour and 4-fold reduction in spleen, highlighting the importance of liposome design.

Targeted siRNA or antisense molecules can be effective but the high charge restricts transfer across cell membranes. Adding ligands enables a Trojan horse effect so a drug can cross cell membranes. For example, antibody-targeted coated cationic liposomes can be used to inhibit anaplastic lymphoma kinase (ALK) in neuroblastima-bearing mice with anti-GD2-targetted CCLs entrapping ALK-siRNA. Free siRNA cannot cross cells but can in a nanoformulation.

A brief history (and reality check) of the time it has taken to develop nanomedicines starts with the first description of liposomes in the early 1960s, which became the foundation of many formulations. Liposomes are 100 nm nanoparticle spheres (visicles) consisting of a phospholipid shell where one end is hydrophobic (usually the outer surface) and one is hydrophilic, enclosing an internal water phase. Drug molecules can be either encapsulated in the water phase or entrapped in the lipid shell. See Figure 3.

Figure 3: Cross Section of Liposome Used for Drug Delivery

Figure 3: Cross Section of Liposome Used for Drug Delivery

Source: http://en.wikipedia.org/wiki/Liposome

Further research led to the development of "stealth liposomes" in 1987 that used polyethylene glycol (PEG) studding on the outer coating to evade the mononuclear phagocyte immune system. AmBisome was approved in 1990, SMANCS (styrene maleic acid neocarzinostatin) in 1993 and Doxil in 1995. Nano-based drug delivery systems began entering mainstream medicine after 2005 and by 2011 there are over 38 nano products on market (worth $6.8 billion annually) with generic systems on the horizon.

The challenge for nanoformulations is to get an appropriate drug using appropriate delivery system that is the right size (not damaging other tissue) with low toxicit, for sufficient duration to solve an unmet medical need.

Crucially this needs to be at a sufficiently low cost to make it usable in a way that is safer and more effective than current treatments. Involvement of Indian companies has successfully radically reduced costs in many areas. In addition to reducing antiretroviral treatment from $10,000 to under $100 per year, the cost of hepatitis vaccinations have been reduced from $20 to $1, psoriasis treatment has been reduced from $20,000 to $100 and cataract surgery is carried out at 1% of the UK cost.

While the political aspects of new technology for infectious diseases have a high level of collaboration between countries at end stage distribution, the level is low for the early stages of research and development. The research presented at this workshop is going some way to address this.

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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.
 
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