A significant number of promising pharmaceuticals are organic molecules with painfully low solubility in water. As most routes of drug administration involve aqueous substances such as blood, this is a big problem. Drug delivery research focusses on effective delivery of such pharmaceuticals to improve the treatment regime for the patient or to improve the efficacy of the treatment. For example, a way to improve a treatment regime may be switching from long intravenous infusions to a pill that could be taken orally. It sounds simple but actually switching from a drug that goes directly into the bloodstream to a pill that must be absorbed through the digestive system is fraught with difficulties.
Chemotherapy is notorious for its side-effects, generally caused by a drug acting in an area of the body that’s not the key target of treatment. This makes any treatment regime far more unpleasant and is potentially wasteful of expensive drugs. More effective delivery of pharmaceuticals can reduce side effects by reducing the dose required by careful targeting to the site of action. This means that more of the drug can accumulate at the site of action and hopefully have greater effect. Targeting can be split into two methods, active and passive. Active targeting makes use of a molecule that is attracted to a specific part of the body, for example, iodine to the thyroid gland. By incorporating an active targeting mechanism into a drug delivery system, greater efficacy can be achieved. Passive targeting for cancer therapy makes use of the idea that the tissues that make up solid tumours have leaky blood vessels. This means that certain sizes of molecules can slip through a leak and accumulate in the tumour tissues. Normal tissues have non-leaky blood vessels and so are not effected in the same way. This is called the Enhanced Permability and Retention (EPR) effect.
There are many types of drug delivery systems that can make use of the EPR effect, in many different stages of development from purely bench research through to clinical trials. Large polymeric structures such as dendrimers and dendronized polymers are particularly popular.
Research from two labs in Italy and Israel by Clementi, Miller, Mero, Satchi-Fainaro and Pasut has investigated the idea of using both active and passive targeting for treatment of bone cancer . They combine two drugs, paclitaxel, and alendronate. Paclitaxel is a well known anti-cancer agent with poor water solubility (called a hydrophobic molecule, the opposite is hydrophilic – water loving), and is often formulated with Cremophor EL, a pegylated caster oil derivative. Patients are often afflicted by side effects from both the drug and its delivery system which can provoke allergic responses. Alendronate is an aminobiphosphonate used for the treatment of bone metastases and osteoporosis. The phosphonate group makes it ideal for interaction with bone which contains high levels of calcium and phosphorus in the mineral hydroxyapetite. These two drugs were attached to either end of poly(ethylene glycol)-poly (glutamate acid), where the poly (glutamate) was a dendritic polymer or ‘dendron’, having a branched structure. In each molecule, 1 paclitaxel group and as many alentronate groups as dendron endgroups were attached, in this case 4.
The big questions when devising such a drug delivery system are whether the polymer conjugate is soluble in water (for intravenous delivery), whether the conjugate is stable in water-based solutions, the size of the conjugate (to get tangled up in the tumour tissue), and whether the conjugate offers any advantage over standard treatment methods, in this case paclitaxel in Cremophor EL. Toxicity is also a big issue – does the conjugate have higher toxicity or different toxicity than the drugs alone or in the standard treatment? Obviously here the goal is targetting a specific type of tumour so does the conjugate allow that to happen.
In this case conjugate seems to have formed micelles, allowing the hydrophobic paclitaxel groups to hide in the interior, with the hydrophillic alendronate groups on the outside. This kind of system is quite common for linear block copolymers, partially dendronised systems are becoming more popular because you can attach more drug molecules to the larger number of end groups. I say seems to have formed because that’s what the table of contents graphic implies, but the word micelle isn’t used frequently, except in the caption for figure 2 and the discussion. Perhaps it would be safer to use the term aggregates! Poly(ethylene glycol) is quite a hydrophillic polymer and as such may be less inclined to form micelles, something like hydrophobic poly(caprolactone) would be far more likely to form micelles.
The drug loading achieved was good with 4.7 % (w/w) paclitaxel and 11 % (w/w) alendronate. The conjugates had a hydrodynamic diameter of 200 nm, and reasonable plasma stability. Studies measuring the quantity of the conjugate bonded to hydroxylapatite, the mineral found in bone, showed that incorporation of the alendronate lead to high (75 – 95%) binding very rapidly. Hydroxylapatite was used to mimic bone tissue. Further, the conjugates did not damage red blood cells when exposed to rat red blood cells. Activity of the conjugates was tested by cell culture studies with human prostate adenocarcinoma cells and critically the cytotoxicity (how well the drug killed the cancer cells) was comparable to that of paclitaxel and alendronate not attached to a polymer conjugate. Sometimes conjugation reduces the activity of the drug but that doesn’t mean failure if you can use the polymer to get more of the drug to the site of action. In all this is a nice study that specifically designs a polymer to act as a carrier for two drug molecules, one to kill cancer cells, the other to specifically bind to bone.
1 Maeda, H., Wu, J., Sawa, T., Matsumura, Y., & Hori, K. (2000). Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review Journal of Controlled Release, 65 (1-2), 271-284 DOI: 10.1016/S0168-3659(99)00248-5
2 Clementi C, Miller K, Mero A, Satchi-Fainaro R, & Pasut G (2011). Dendritic Poly(ethylene glycol) Bearing Paclitaxel and Alendronate for Targeting Bone Neoplasms. Molecular pharmaceutics PMID: 21608527
3 Dendrimers differ from linear polymers in that dendrimers have a branched structure (tree-like) with lots of end groups, whereas linear polymers usually have two end groups.