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Use of Polymer Therapeutics to Improve Drug Targeting& Release

Overview of polymer therapeutics

Polymers are the general term for the huge group of carbon-based organiccompounds that include proteins, carbohydrates and nucleic acids (Campbell etal., 1999). Combining existing drugs with biological polymers results in anew biochemical entity which has been called a polymer-drug conjugate. Themethod by which researchers are using polymer-drug conjugates to improve drugdelivery and release is commonly termed as 'polymer therapeutics' (Modi etal., 2004).

Around a dozen different products are now in clinical trials at differentstages, and have been widely shown to increase targeting, release, and thusbioavailability of the drug by increasing its solubility, its half-life, orboth simultaneously.

More mainstream drug delivery methods involve using antibodies orliposomes to carry the drug being deposited into the body. A common problemwith these methods is that drugs can get 'lost' in the patient's body due tothe lack of targeting (Henry, 2002). Liposomes can be engulfed by the body's macrophages,or can quickly extravasate out of the bloodstream into non-target tissue.

The methods of delivering drugs, it seems, it equally as important as thenature of the drug itself. This essay will look at some examples of recentresearch about drug targeting and release using polymers. We will then look inmore depth at two examples of diseases being researched; improving targeting inlung cancer, and improving release in schizophrenia.

Current research intopolymer-based drug targeting

A novel way of inserting and targeting drugs is by implanting themalongside a polymer. New technologies currently being tested are allowing micro-scaleimplants to be manufactured, which can then be inserted into the body for varyingperiods of time (LaVan et al., 2003). The design of implants can bemanipulated to accommodate different pharmokinetic. For example, some willrelease regular bursts of dosage, whilst others will constantly release astream of drug. Some might biodegrade over time, whilst other might be removedfrom the body, refilled, and reinserted (LaVan et al., 2003). While muchof this essay concentrates on polymer therapeutics for serious diseases, thiskind of technology might one day be included in the simplest of oral drugs likeparacetamol, to help drugs attach to the intestinal wall and access thebloodstream faster. As one review author has pointed out, lectin-modifiedmucoadhesives have already been shown to bind to the intestine's mucosal wall,and so could well be incorporated into a conjugate for oral drug administration(LaVan et al., 2003).

At a recent conference, Dr Kataoka from the University of Tokyo explainedhis research into the use of the alcohol ethylene glycol and the amino acid,aspartic acid, to help target certain drug delivery (Senter & Kopecek,2004). His work focuses on improving photosensitive drugs administered formedical imaging, and his results have shown efficiency is significantlyimproved by the binding of polymers. The dilute solutions of ethylene glycoland aspartic acid copolymers form tiny micelles of different shapes dependingon the hydrophilic nature of the compounds, which then encase the required drug(Senter & Kopecek, 2004).

Current research intopolymer-based drug release

Polymers are also being utilised to prolong the breakdown and release ofdrugs into the body. Again, these techniques are largely being investigated inregards to improving cancer chemotherapy.

Sipos et al., (1997), were one of the early groups to look at theapplications of implanted polymers to aid the treatment of brain tumours. Thetraditional drug carmustine was combined with carboxyphenoxypropane polymerizedwith sebacic acid. This was designed to administer long-lasting, high-intensitydoses of carmustine into cancerous tissue. The conjugate improved the releaseof the drug (Sipos et al., 1997). An interesting issue this study raisedwas the importance of balancing the ratio of polymers if more than two areincluded in the conjugate. Testing in monkeys, the authors found that the ratioof carboxyphenoxypropane to sebacic acid was optimal at 20:80, seeminglybecause this implant was better tolerated.

One recent addition to the ranks of polymers possible for formingconjugates is hydrogels (LaVan et al., 2003). These are substancesderived from polysaccharides and naturally-occurring proteins, which formtogether to imitate an extracellular matrix (Balakrishnan & Jayakrishnan,2005). The properties of hydrogels can be fixed so that drug release can occurat certain times: Different hydrogels can be sensitive to applied charges orspecific antigens at which they may dissolve, thus releasing the drug, orswell, absorbing the drug (LaVan et al., 2003).

Balakrishnan and Jayakrishnan (2005) studied the viability of using alginateand gelatine derivatives. Alginates are linear polymers composed of mannuronicacid and guluronic acid, and produced by various species of brown seaweeds(Chaplin, 2005a). Gelatine is another mixture of proteins. Its structure isderived from collagen, is high in glycine residues as well as proline andhydroxyproline. Its properties mean it is widely used, such as here, as agelling agent (Chaplin, 2005b). The authors linked these two substances to thedrug primaquine, a treatment for malaria. They found the gel cross-linked thedrug effectively, whilst being fully biocompatible and degraded naturally(Balakrishnan & Jayakrishnan, 2005).

Example 1: Uses of polymertherapeutics in treating lung cancer

Treating cancer diseases is fraught with difficulties. Traditionaltherapies of chemotherapy or radiation will inadvertently become toxic tohealthy tissue as well as to cancerous cells. It is also difficult for thesemethods to systematically kill every diseased cell, leaving some to proliferateand allow resurgence of the tumour (Alberts et al., 1994). The uses ofpolymer therapeutics in cancer are therefore primarily aimed towards improvingdrug targeting characteristics.

The pharmaceutical company Cell Therapeutics produces a polymer-drugconjugate for treating lung cancer (Senter & Kopecek, 2004). Their product,Xyotax, is formed by fusing the drug paclitaxel with the protein polymerpolyglutamic acid, and is currently in the latter stages of Phase III clinicaltrials. Xyotax has shown greater uptake in tumour tissue and has minimised theoverall toxicity of chemotherapy to the patients (Senter & Kopecek, 2004).

Liposomal systems are currently a large area of research for targetingcancerous cells. As discussed in the overview however, liposomes are liable to'leak' out of the bloodstream away from the target tissue. New research hasshown that coating liposomes with polysaccharides improves their deliveryaccuracy. Tested in guinea pigs, liposomes linked to amylopectin residues werefound to be taken up more in alveolar tissue than elsewhere in the body. Also,they are more rapidly localised to the cancerous tissue than liposomes withoutlinked polymers (Sihorkar & Vyas, 2001).

Example 2: Uses of polymertherapeutics in treating schizophrenia

Schizophrenia is a mental disorder affecting 1% of the population (Kahn,2003). Problems associated with the treatment of patients is that manysufferers will stop taking their prescription, often as a direct result oftheir symptoms. Subsequently, there is a need for drugs which will releaseslowly, persisting for long periods in the bloodstream between hospital visits.This is obviously a very serious issue when suicide occurs in 10% of sufferers'lifetimes (Freedman, 2003). Hence, the goal of polymer therapeutics in schizophreniais to improve drug release kinetics over a longer time period.

As Kahn (2003) writes, polylactide glycolide has been utilised to createa slow-release medication system. Because the polymer is a biological molecule,it dissolves safely in the body over time to form glycolic acid and lacticacid, both standard waste products of the body (Kahn, 2003).

Other researchers are working on implanting traditional schizophrenia drugslike haloperidol, into the body in combination with a slowly-biodegradingpolymer. A paper written in 2002 by Siegel et al., looked at thebioactivity of such a conjugate in rats. They found that the implants releasedthe drug steadily over the course of five months. Roderigues et al.,(1999) carried out research on conjugating the lung cancer drug doxorubicin toa form of polyethylene glycol, focussing on the type of linkage to use betweenthe two. Doxorubicin and polyethylene glycol were manufactured together with eithera hydrazone or an amide linkage. In vitro experimentation elucidated that onlythe conjugate expressing the hydrazone linkage demonstrated cellular activity.This may be because this type of bond might be more easily degraded by endocytosisonce the conjugate is inside the tumour cell. This paper shows the importanceof the details concerning the manufacture of conjugates, demonstrating that theprocess is far from straight-forward.

An injectable formulation of the drug risperidone held within a polymermatrix is another method currently being investigated. Weekly injections insertthe drug-polymer conjugate which degrades very slowly, releasing risperidoneover the course of six or seven weeks (Sakkas, 2003).

Concluding remarks

There seems little doubt from the research done here that there are hugebenefits to the development of polymers for drug targeting and release. We haveseen that this might be useful for pioneering new cancer therapy and otherserious diseases. The beauty of polymer-drug conjugates is that they are makingthe most of using conventional drugs, rather than starting from scratch tocreate brand new compounds.

To simply find polymers which can successfully bind with a drug to helptarget and release it seems far from the whole story. Biomedical researchers haverecognised the need to manufacture the conjugate according to how rapidly theywant it to break down, for example by putting in more peptide linkages to slowthe action of cellular proteases (Henry, 2002). They need to select polymerswhich will target unhealthy cells or particular tissues of the body. There isalso a need to conduct more research into the optimum concentrations and ratiosof drug to the single or dual polymers, to prevent heightened toxicity and accumulationin the body.

From the research done here, a relatively small amount for such a largefield, it seems likely that the next decade will see some of these newtherapies break out into mainstream medical use, and see even more possible conjugatesgo into clinical trials. There seems to be considerable potential that this newera of therapy may revolutionise a number of different fields of medicine, inparticular the administration of drugs to treat cancer.

Bibliography

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Chaplin, M.(2005a). Water Structure & Behaviour: Alginate. London SouthbankUniversity WebPages. http://www.lsbu.ac.uk/water/hyalg.html

Chaplin, M.(2005b). Water Structure & Behaviour: Gelatin. London SouthbankUniversity WebPages. http://www.lsbu.ac.uk/water/hygel.html

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Sihorkar, V.& Vyas, S.P. (2001). Potential of polysaccharide-anchored liposomes in drugdelivery, targeting and immunization. Journal of Pharmacy and PharmaceuticalScience, 4 (2), pp.138-158.

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