Chapter 9
Polymers in Biotechnology Raphael M. Ottenbrite
Downloaded by UNIV LAVAL on October 21, 2015 | http://pubs.acs.org Publication Date: January 7, 1988 | doi: 10.1021/bk-1988-0362.ch009
Department of Chemistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23284
Macromolecules comprise many of the natural materials found in living matter. The most important and abundant are the proteins, nucleic acids and polysaccharides. These and other basic biomolecules were selected during the course of biological evolution for their capacity to perform specific functions. Consequently, specific biomacromolecules have evolved that function as membranes for compartmentalization, as enzymes and coenzymes for reaction catalysis, as polynucleic acids for memory and protein replication, and as polysaccharides for connective tissue, energy and structural components. The elucidation of the complex function, structure, and modes of reaction of these biomacromolecules has been a major goal of many scientists. Recently it was discovered that some synthetic polymeric materials have physicochemical properties that are compatible with biological systems. Subsequently, polymer chemists in collaboration with basic scientists are developing new synthetic materials with attention to synthesis, macromolecular design, structure-reactivity relationships, molecular weights, solubilities and other physicochemical properties related to physiological activity and toxicity. Similarly, advances in the development of synthetic polymeric materials for artificial skin, sutures, prosthetic devices and surgical implants are being made by polymer chemists in collaboration with scientists in surgery, pathology and immunology. Consequently, polymers and basic polymer science itself, are now playing an important role in the area of medical treatment. Although polymers have been used for a considerable length of time for such biomedical applications as prosthetic devices, cosmetic implants, and enteric coatings, only recently have their importance been recognized for drugs and for drug administration. Therefore, drug research has moved beyond the biochemistry laboratories and is securing its own position in polymer chemistry. The reason is that the requirements for any materials utilized for biological application are exceptionally demanding; they are required to be extremely pure and have specific physicochemical properties. Characteristics
0097-6156/88/0362-0122$06.00/0 © 1988 American Chemical Society
In The Impact of Chemistry on Biotechnology; Phillips, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1988.
Downloaded by UNIV LAVAL on October 21, 2015 | http://pubs.acs.org Publication Date: January 7, 1988 | doi: 10.1021/bk-1988-0362.ch009
9. O T T E N B R I T E
Polymers in Biotechnology
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t h a t are very important i n these m a t e r i a l s a r e , biocompatability, d u r a b i l i t y , n o n t o x i c i t y , and b i o d e g r a d a b i l i t y . Polymer c h e m i s t s a r e now p l a y i n g a unique and i m p o r t a n t f u n c t i o n i n d e v e l o p i n g new monomers, polymers and c o p o l y m e r s , e v a l u a t i n g the p h y s i c o c h e m i c a l p r o p e r t i e s , and d e t e r m i n i n g how t h e s e p r o p e r t i e s r e l a t e to b i o l o g i c a l systems which a r e i n need o f m e d i c a l a s s i s t ance. N o r m a l l y , u n l e s s t o p i c a l l y a c t i v e , a drug i s a d m i n i s t e r e d by means o f i n g e s t i o n , i n j e c t i o n , o r by i n f u s i o n . In a l l c a s e s , the r e a g e n t e n t e r s the body and i s t r a n s p o r t e d t o the d i s e a s e d s i t e i n time dependent c o n c e n t r a t i o n s . A drug i s g e n e r a l l y distributed t h r o u g h o u t an organism v i a the aqueous phase o f the b l o o d plasma o r l i p i d phases o f the b o d y , r e a c h i n g t h e t i s s u e s o f an organ a t a r a t e determined by b l o o d f l o w through t h a t organ and by the r a t e o f passage o f the drug m o l e c u l e a c r o s s t h e c a p i l l a r y bed and i n t o the tissue c e l l s . Most o f the drug i s e x c r e t e d , h e l d i n v a r i o u s f l u i d compartments, o r l o c a l i z e d i n s u b c e l l u l a r a r e a s such as macromolec u l a r s u r f a c e s and i n f a t d e p o s i t s by a d s o r p t i v e o r partition processes. Even w i t h i n the t a r g e t t i s s u e , c e l l u l a r fractionation s t u d i e s r e v e a l t h a t most drug m o l e c u l e s a r e a s s o c i a t e d w i t h s t r u c t ures not i n v o l v e d w i t h t h e s p e c i f i c drug a c t i v i t y . C o n s e q u e n t l y , polymer s c i e n t i s t s have become i n v o l v e d i n d e v e l o p i n g new and improved methods o f drug d e l i v e r y as w e l l as s p e c i ficity. The most d i f f i c u l t problem i n drug a d m i n i s t r a t i o n is g e t t i n g a s u f f i c i e n t q u a n t i t y o f agent t o the i n f l i c t e d s i t e a t a proper dosage. Ingestion and injection methods often require r e p e a t e d a d m i n i s t r a t i o n wherein the whole body becomes i n f u s e d w i t h a h i g h c o n c e n t r a t i o n o f drug t h a t s l o w l y d i s s i p a t e s . The optimum t h e r a p e u t i c l e v e l s a r e o n l y r e a l i z e d when the a s c e n d i n g o r d e s c e n d i n g c o n c e n t r a t i o n s pass through t h i s " t h e r a p e u t i c window". Periods o f o v e r - m e d i c a t i o n o f t e n r e s u l t s i n a c u t e s i d e e f f e c t s , w i t h no therapeutic value. The u l t i m a t e answer i s t o a c h i e v e s i t e s p e c i f i c drugs which w i l l be d e l i v e r e d a t both an e f f e c t i v e c o n c e n t r a t i o n and a t an o p t i m a l r a t e . Research i s now d i r e c t e d toward the development o f s y n t h e t i c polymers which w i l l be u t i l i z e d f o r c o n t r o l l e d drug r e l e a s e and transport. A number o f t e c h n i q u e s have been d e v i s e d t o a c h i e v e z e r o - o r d e r drug d e l i v e r y i n an e f f o r t t o a v o i d the problems i n h e r e n t w i t h the p r e s e n t methods o f a d m i n i s t r a t i o n . The polymer systems t h a t a r e b e i n g e x p l o r e d f o r p h a r m a c e u t i c a l a p p l i c a t i o n s i n c l u d e ; (a) polymer d r u g s : polymers o r copolymers that are physiologically active themselves, (b) drug-carrying polymers: polymers t h a t have a c t i v e drugs bound t o a p a r e n t polymer backbone; t h e s e may be drugs p e r m i n e n t l y o r s e m i p e r m i n e n t l y a t t a c h e d t o the polymer backbone o r pendent t o i t , (c) time-release drug polymers: polymers used f o r c o n t r o l l e d r e l e a s e o f t h e d r u g ; the drug may be e n c a p s u l a t e d w i t h water s o l u b l e polymer c o a t i n g s which d i s s o l v e a t d i f f e r e n t r a t e s and r e l e a s e the drug a t v a r i o u s t i m e s , o r the drug may be imbedded i n t o a polymer m a t r i x from which it d i f f u s e s a t s p e c i f i c r a t e s , (d) s i t e - s p e c i f i c d r u g s : polymers t h a t have s p e c i a l c h e m i c a l groups a t t a c h e d t o t h e polymer c a r r y i n g the d r u g ; t h e s e groups can combine w i t h s p e c i f i c r e c e p t o r s i t e s on p r o t e i n , c e l l s u r f a c e s o r i n the l i p i d a r e a s t o a c h i e v e s p e c i f i c b i n d i n g and drug d e l i v e r y .
In The Impact of Chemistry on Biotechnology; Phillips, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1988.
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T H E IMPACT O F CHEMISTRY ON BIOTECHNOLOGY
A l t h o u g h s y n t h e t i c polymers a l r e a d y p l a y a r o l e i n b i o l o g i c a l s y s t e m s , i t i s e v i d e n t t h a t our u t i l i z a t i o n o f t h e s e s u b s t a n c e s f o r t h e s e purposes i s o n l y i n i t s i n f a n c y . In o r d e r t o make polymers more e f f e c t i v e , much more has t o be u n d e r s t o o d about toxicities, specificity, structure-relationships, m o l e c u l a r w e i g h t and other physicochemical p r o p e r t i e s . New polymers a r e r e q u i r e d t h a t w i l l compliment the d e l i c a t e b a l a n c e o f the b i o l o g i c a l s y s t e m s . Further r e s e a r c h i n t o polymer s t a b i l i t y and b i © c o m p a t i b i l i t y f o r implants and p h a r m a c o k i n e t i c s o f polymers f o r c o n t r o l l e d drug r e l e a s e and longer d u r a t i o n r e l e a s e are needed. T h u s , we see b e f o r e us an e x c i t i n g and unique c h a l l e n g e to be met which w i l l require the r e s o u r c e s o f s e v e r a l s c i e n t i f i c d i s c i p l i n e s , but w i t h o u t s t a n d i n g rewards t o be a c h i e v e d . 1987
Downloaded by UNIV LAVAL on October 21, 2015 | http://pubs.acs.org Publication Date: January 7, 1988 | doi: 10.1021/bk-1988-0362.ch009
RECEIVED September 19,
In The Impact of Chemistry on Biotechnology; Phillips, M., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1988.
