Biologically Active Polymers - ACS Symposium Series (ACS

Chapter 1

Biologically Active Polymers Raphael M. Ottenbrite

Downloaded by OPEN UNIV MILTON KEYNES on July 1, 2013 | http://pubs.acs.org Publication Date: August 15, 1991 | doi: 10.1021/bk-1991-0469.ch001

Department of Chemistry, High Technology Materials Center, Virginia Commonwealth University, Richmond, V A 23284

Interest continues to grow in polymers that have inherent biological activity or polymers which are covalently attached to well known drugs. This paper provides an introduction to these types of materials and a general review of the different types of polymeric drugs, polymeric drug conjugates, polymeric prodrugs, and targeted polymeric drugs which can be classified as biologically active polymers.

Drug delivery systems are ideally devised to disseminate a drug when and where it is needed and at minimum dose levels. Polymeric drugs and delivery systems provide that possibility through several different approaches. Polymeric drugs, polymeric drug conjugates or drug carriers, polymeric prodrug systems, bioerodible matrices, diffusion through membranes orfrommonolithic devices, and osmotic pumps are all drug delivery options. This paper will review some of the materials and approaches to using polymers as drugs themselves, conjugated to well known drugs, prodrug systems, and targeted drug carriers. Polymeric Drugs. Polymeric drugs are macromolecules that elicit biological activity (1). Many synthetic polymers are biologically inert. However, some exhibit toxicity, while others exhibit a wide range of therapeutic activities. There are three kinds of polymer drugs: polycations, polyanions, and polynucleotides. Polycationic polymers. These are macromolecules that have electropositive groups attached to the polymer chain or pendant to the chain. These materials are active against a number of bacteria and fungi. However, due to their inherent toxicity to animal species through their destructive interaction with cell membranes they are 0097-6156/91/0469-0003$06.00/0 © 1991 American Chemical Society

In Polymeric Drugs and Drug Delivery Systems; Dunn, R., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1991.

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only used topically (2). Recent reports indicate that they can enhance cellular antigen uptake and exhibit antitumor activity against Ehrlich carcinoma. Polyanionic polymers. Polyelectrolytes with negative charges on the polymer can also function as drugs. These polymers are much less toxic. Both natural polyanions, such as heparin and heparinoids, and synthetic polyanions such as, poly(acrylic acid), exhibit a variety of biological activity (5). For example, poly(divinyl ether-co-maleic anhydride) exhibits antiviral, antimicrobial and antifungal activity. It is best known for activity against a number of animal tumor models most notable Lewis lung carcinoma, Ehrlich carcinoma, and Friend leukemia. One mechanism of activity is the activation of macrophages and augmentation of natural killer cell activity. Other polycarboxylates, such as Carbetimer, poly(maleic anhydride-cocyclohexyl-l,6-dioxepin) and poly(maleic anhydride-co-4-methylpentenane), elicit a similar broad spectrum of activity. Polyanionic polymers can enter into biological functions by distribution throughout the host and they behave similar to proteins, glycoproteins and polynucleotides which modulate a number of biological responses related to the host defense mechanism. These are enhanced immune responses, and activation of the reticuloendothelial system (RES) macrophages. The synthetic polymer which has received the most interest is divinyl ethermaleic anhydride copolymer, commonly referred to as pyran copolymer due to the tetrahydropyran ring which forms during polymerizaton. In the literature it is also referred to by the acronym D I V E M A (divinyl ether-maleic anhydride copolymer) and, more recently, as M V E (maleic anhydride-vinyl ether copolymer). Pyran was first reported by Butler in 1960 and submitted to the NIH screen (4). Pyran showed significant activity and was designated as N S C 46015 by the National Cancer Institute. It has been under investigation for use in cancer chemotherapy and has also exhibited a wide range of other biological activities. Pyran has been reported to have interferon inducing capacity and to be active against a number of viruses including Friend leukemia, Rauscher leukemia, Maloney sarcoma, polyoma, vesicular stomatitis, Mengo and encephalomyo-carditis. A number of investigations have clearly demonstrated that the structure and molecular weight of synthetic polyanions are directly related to biological activity and toxicity. Breslow showed that the acute toxicity caused by pyran in mice increased with increased molecular weight (5). Biological activity data of pyran fractions (2,500-32,000) indicated that molecular weights up to 15,000 stimulated RES whereas higher molecular weight fractions suppressed R E S , resulting in biphasic response. It was found that the level of serum glutamic pyruvate transaminase, which is a measure of liver damage, also increased with molecular weight, as did inhibition of drug metabolism and sensitization to endotoxin. However, the activities against Lewis lung and Ehrlich ascites tumor were shown to be independent of molecular weight. Recently, considerable evidence has emerged that implicates the macrophage as a major effector of tumor cytotoxicity and/or cytostasis. Both synthetic



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Biologically Active Polymers

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reticuloendothelial stimulants such as poly(acrylic acid-a/f-maleic anhydride), pyran and poly(riboinosinic-polycytidylic acids)s as well as biologic reticuloendothelial stimulants are known to enhance macrophage function as well as to induce resistance of tumor growth. Moreover, macrophages from animals treated with polyanionic stimulants have been demonstrated to be cytostatic and/or cytotoxic for tumor cells while demonstrating quantitatively less cytotoxicity for normal cells (6). Presently there are two polyanionic polymers, M V E - 2 and Carbetimer, that have undergone considerable clinical evaluation as antitumor agents. Another important family of anionic polymeric drugs are the heparins and heparinoids which have mainly sulfonate groups. These have been used primarily as anticoagulants but also exhibit antimitotic effects. Recently extrasulfated heparin derived from a heparine fraction was reported to have excellent anti-clotting and anti-Xa activity (7). New fluorescent derivitized heparine molecules, without alteration of their bioactivity, are available for bioevaluations such as the von Willebrand Factor during surgery (8). More recently chitosan polymers which are derivatives of chitin materials have evoked interest due to their bioactivity and biodegradability. For example, Ncarboxybutyl chitosan has been show to effectively promote wound healing (9). Acetate, and butyrate derivatives of chitosan have decreased blood clotting time significantly (10). Polynucleotides. Polynucleotides are potent interferon inducers. A mismatched, double-stranded synthetic polyribonucleotide ampligen and the double-stranded acids, polyadenylic-polyuridylic acid and polyinosinic-polycytidylic acids have been widely studied for cancer therapy(77). Although these materials elicit excellent activity with murine rodents, therapeutic effects are dramatically decreased within primates. Since nucleic acids and enzymes play such a large role in chromosome replication during mitosis, a considerable amount of research has been conducted in this area to control viruses. On the molecular level, analogues of nucleic acids are capable of forming complexes with adenine, cytosine, uracil, thymine, and guanine. Through complexation, these nucleic acid analogues are potential inhibitors of biosyntheses that require nucleic acids as templates. The polyvinyl analogues of nucleic acids are one of the few polymers that have been tested in living systems to determine their bioeffects. The most thoroughly investigated polymer is poly(vinyladenine), which has been reported to be effective against viral leukemia, chemically induced leukemia, and infections caused by other viruses (72). The inhibition of viruses by the complexation of nucleic acids with their polymer analogues is apparently very specific. For example, poly(9vinyladenine) inhibits R N A viral replication through the reverse transcriptase step, whereas poly(9-vinylguanine) is ineffective against viruses. These materials still have clinical interest.


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Polymeric Drug Conjugates or Drug Carriers. Many potentially effective drugs cannot be used because of host elimination or rapid metabolization. In some instances this can be amended by using drug-polymer conjugates (13,14,15,16). The drug is covalently bonded to an appropriate polymer carrier. These large molecules diffuse more slowly and are adsorbed at distinct pharmacological interfaces. Consequently, polymer-drug conjugates can prolong therapy at sustained dosages. The major attributes of polymeric drug carriers are their depot effects, unique pharmacokinetics, body distribution, and pharmacological efficacy. Most medications are micromolecular in size and are relatively free to diffuse throughout the biological system. Consequently, drugs have been inherently difficult to administer in a localized, concentrated mode within the primary target tissues and organs. Polymers, however, diffuse slowly and are often absorbed at interfaces, the attachment of pharmaceutical moieties can produce a biopolymer with distinct pharmacological behavior. These polymeric drug carriers have desirable properties such as sustained therapy, slow release, prolonged activity, and drug latentation. A model for pharmacologically active polymer drug carriers, similar to that shown in Figure 1, has been developed (17). In this schematic representation, four different groups are attached to a biostable or biodegradable polymer backbone. One group is the pharmacon or drug, the second is a spacing group, the third is a transport system, and the fourth is a group to solubilize the entire biopolymer system. The pharmacon is the entity that elicits the physiological response. It can be attached permanently by a stable bond between the drug and the polymer, or it can be temporarily attached and removed by hydrolysis or by enzymatic processes. The transport system for these soluble polymer drug carriers can be made specific for certain tissue cells with homing or targeting moieties such as pH-sensitive groups or receptor-active components, such as antibody-antigent recognition. Solubilizing groups (such as carboxylates, quaternary amines, and sulfonates) are added to increase the hydrophilicity and solubility of the whole macromolecular system in aqueous media while nonpolar groups enhance the hydrophobic character and solubility in lipid regions. The specificity of polymer pharmacokinetics is related to the molecular size, which alters the transport rate across compartmental barriers (18). B y controlling the molecular weight of a polymer drug carrier, it is possible to regulate whether the drug passes through blood-membrane barriers, is excreted by the kidney, or is accumulated in the lymph, spleen, liver, or other organs. The fundamental macromolecular transport theory of biopolymers through tissues has been successfully applied to the design, fabrication, and prediction of in vivo performance of polymer drug-delivery systems. Consequentiy, based on the molecular weight, conjugate polymer drug carriers have been developed to perform more specifically than the drug alone. Many other variables, such as composition of the polymer chain, structure, polyelectrolytic character, and solubility, can also effect polymer behavior.



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Soluble polymer backbone w

*

Spacer

Biodegradable linkage Drug

Targeting moiety Cell-specific enhanced membrane interaction

Figure 1. Model for polymer drug carrier.



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Probably the most promising polymeric drug carrier system involves polysaccharide molecules. These are natural polymers and are often biodegradable to products that are useful to the host or easily eliminated by the host. Dextrans have been the most extensively used polysaccharide for macromolecular prodrug preparations (79). These materials are biocompatible and the in vivo fate is directiy related to their molecular weight. Moreover these macromolecules can be easily targetted to the hepatocytes with D-mannose or L-fucose (20). Another polysaccharide system that has received considerable interest is the chitosans which are water soluble derivatives of chitin. These materials appear to be very biocompatible and degradable and so are potentially excellent candidates as polymeric drug systems (27). Recently poly(amino acids) as polymeric drug carriers has increased in use as they form water soluble polymers and hydrophilic gels. Both homopolymers and copolymers have been used. Since they are similar to naturally occuring proteins, the potential biodegradability of poly(amino acids) offers an advantage over the nondegradable synthetic carbon-carbon backbone polymers. The homopolymers of poly(alpha-amino acid)s arc usually nonimmunogenic while copolymers with two or more amino acids can be immunogenic. Several poly(amino acid) drug conjugates that have been prepared include poly(L-glutamic acid)-adriamycin and poly (Llysine)-methotrexate (22). Polymeric Prodrugs. Polymeric prodrugs are designed to protect against rapid elimination or metabolization by adding a protective polymer to the therapeutic material. Therapeutic activity is usually lost with this attachment and reinstated with the removal of the protective group. The protective group is designed to be easily removed, usually by hydrolysis. Prodrugs are readily prepared with polymers similar to a polymer drug carrier. Temporary attachment of a pharmacon is necessary if the drug is active only in the free form. A drug which is active only after being cleaved form the polymer chain is called a prodrug. Temporary attachment usually involves a hydrolyzable bond such as an anhydride, ester, acetal, or orthoester. Permanent attachment of the drug moiety is generally used when the drug exhibits activity in the attached form. The pharmacon is usually attached away from the main polymer chain and other pendent groups by means of a spacer moiety that allows for more efficient hydrolysis. For example, catecholamines are ineffective when bonded directly to poly(acrylic acid) but affect heart rates and muscle contractions when attached away from the backbone of the macromolecular carrier. Similarly, isoproterenol elicits a pharmacologic response only when coupled to a polymer by a pendent group. One of the most successful conjugate polymer systems was developed by Duncan and Kopecek (23). The polymer carrier used in their system is poly [iV(2hydroxypropyl) methacrylamide] a biocompatible polymer that was originally developed as a plasma extender. They have evaluated a number of polymer conjugated drugs for cancer chemotherapy with interesting results. The attachment of the drug is through a peptidyl spacer pendent to the polymer backbone. These peptides links arc stable in aqueous media but are readily hydrolyzed intracellularly


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by lysosomal enzymes. This method provided effective cell specific delivery. Duncan and Kopecek were also able to achieve organ specific delivery to the hepatocytes with galactosamine; to the T-lymphocytes with anti-T cell antibodies; and to leukemia cells with fucosylamine (24). Targeted Polymeric Drugs. Polymer drug targeting to a specific biological site is an enormous advantage in drug delivery because only those sites involved are affected by the drug. This precludes the transport throughout the body, which can elicit serious side effects. Ideally, a targetable drug carrier is captured by the target cell to achieve optimum drug delivery while minimizing the exposure to the host. Fluid-phase uptake of macromolecules by cells in general is a slow process, and most administered macromolecules are eliminated from the host before any significant cellular uptake takes place. If, however, the macromolecule contains a moiety that is compatible with a receptor on a specific cell surface, then the macromolecule is attracted to the cell surface and the uptake is enhanced. This maximizes the opportunity for specific-cell capture. This type of cell-specific targeting has been developed; to hepatocytes, with galactosamine; to T lymphocytes, with anti-T cell antibodies; and to mouse leukemia cells, with fucosylamine and other biomolecules. The discovery of monoclonal antibodies and combining them with polymeric prodrugs is the newest approach to overcome the lack of selectivity for disposition in target tissue (23). Recently the selectivity of antibody-targeted polymeric anthracycline antibiotics to T lymphocytes was accomplished (25). In addition decreased immunogenicity of proteinaceous conjugates with IgG and human transferrin has been reported (26). The ultimate fate of drugs and their metabolites is a major concern. If they are not cleared in a reasonable time, they could promote undesirable side effects. Polymer drug carriers are usually nonbiodegradable, and if their size is greater than 40,000 daltons, they could accumulate in the host with the potential of future unwanted effects. The applications of targeted drug carrier systems has not been fully realized. The utilization of the total concept, which includes a biocompatible drug-carrier with selective cell targeting, controlled-drug release, and biodegradability, will provide highly potent drug administration systems for the future. Summary Polymeric drugs and drug delivery technology has emerged during the 1980's to be a commercially attractive method for administering drugs in a controlled and effective mode. The technique is capable of effecting sustained release of a bioactive substance with optimum response, minimum side-effects, and prolonged efficacy. Recently success has been achieved in targeting drugs to a specific organ or site. The 1990's should prove even more exciting with more clinical activity and new polymer designs.


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Literature Cited 1. Anionic Polymeric Drugs; Ottenbrite, R. M.; Donaruma, L. G.; Vogl, O., Eds.; Wiler-Interscience: New York, NY, 1980.. 2. Polymeric Drugs; Donaruma, L. G.; Vogl, O., Eds.; Academic Press, New York, NY, 1978. 3. Ottenbrite, R. M. In Anticancer and Interferon Agents; Marcel Dekker: New York, NY, 1984. 4. Buder, G. B. J. Poly. Sci. 1960, 48, 279. 5. Breslow, D. S. Pure Appl. Chem. 1976, 46103. 6. Ottenbrite, R. M.; Kuus, K.; Kaplan, A. M. J. Macromol. Sci. 1988, A25, 499. 7. Braud, C.; Vert, M.; Petitou M. J. Bioact. Comp. Polymers 1989, 4, 269. 8. Suda, Y.; Sumi, M.; Sobel, M.; Ottenbrite, R. M. J. Bioact. Comp. Polymers 1990, 5, 412. 9. Muzzarelli, R. A. A. et al. J. Bioact. Comp. Polymers 1990, 5, 396. 10. Dutkiewic, J. et al. J. Bioact. Comp. Polymers 1990, 5, 293. 11. Levy, H. B. J. Bioact. Comp. Polymers 1986,1,348. 12. Takamoto, K; Inaki, Y. Functional Monomers and Polymers; Marcel Dekker, Inc.: New York, NY; 1987; 149. 13. Dumitriu, S.; Popa, M.; Dumitriu, M. J. Bioact. Comp. Polymers 1988, 3, 243. 14. Dumitriu, S.; Popa, M.; Dumitriu, M. J. Bioact. Comp. Polymers 1988,3,403. 15. Dumitriu, S.; Popa, M.; Dumitriu, M. J. Bioact. Comp. Polymers 1989,3,57. 16. Dumitriu, S.; Popa, M.; Dumitriu, M. J. Bioact. Comp. Polymers 1989,3,151. 17. Ringsdorf, H. J. Polym. Sci. 1975, 51, 135. 18. Johnson, P.; Lloyd-Jones, J. G. Drug Delivery Systems; Ellis Horwood Ltd.: 1987. 19. Larsen, C. Adv. Drug Delivery Rev. 1989, 3, 103. 20. Schwartz, A. L. CRC Crit. Rev. in Biochem. 1984,16,207. 21. Muzzarelli, R. A.; Weckz, A. M.; Filippini, O.; Lough, C. Carbohydr. Polymers 1989,11,307. 22. Rihova, B. CRC Crit. Rev. in Therapeutic Drug Del. Systems 1985,1,311. 23. Kopecek, J. J. Bioact. Compat. Poly. 1988,3,16, 24. Duncan, R.; Seymour, L. W.; Ulbrich, K.; Kopecek, J. J. Bioact. Compat. Poly. 1988, 3, 4. 25. Rihova, B.; Strohalm, J.; Plocova, D.; Ulbrich, K. J. Bioact. Compat. Polymers 1990, 5, 249. 26. Flanagan, P.A.; Duncan, R.; Rihova, B.; Subr, V.; Kopecek, J.J.Bioact. Compat. Polymers 1990, 5, 151. RECEIVED April 8, 1991


Biologically Active Polymers - ACS Symposium Series (ACS

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