Abstracts of papers

s of papers PARTICULATE SYSTEMS AS CARRIERS FOR SITE-SPECIFIC DRUG DELIVERY: THE STATE OF THE ART D.J.A. Crommelin In the last decade a number of particulate carrier systems have been developed to change the therapeutic efficacy of drugs after intravenous injection. Among these are nanopart i t l e s , liposomes, gelatin and albumin microspheres. The objectives for designing these systems varied widely: from a sustained action to site specific delivery of the encapsulated drug. Cri t ical points for the selection of a carrier system are: I) the ab i l i t y of the carrier-homing device combination to deliver the drug at the desired sites; 2) the acute and chronic tox ic i ty of these systems and their immunogenicity; 3) the preparation and shelf l i f e of the products. For homing devices antibodies and certain glycolipids are under investigation. The results indicate that site specif ic delivery is hampered by the limited ab i l i t y of the carriers to pass the wall of the blood vessels and the strong a f f i n i t y of the cells of the reticulo-endothelial system (RES) for these "foreign" bodies. Therefore, target sites should be located either in the compartment of injection (general circulation) or in the cells of the RES. Distribution kinetics in vivo are susceptible to composit ion, size and charge of the Carrier system. A proper def i n i t i on of the product is therefore essential to obtain results that are suf f ic ient ly reproducible. In this presentation some of the conclusions mentioned above wi l l be i l lustrated and discussed in more detai l . Dept..of Pharmaceutics, Subfaculty of Pharmacy, State of University of Utrecht, Catharijnesingel 60 3511GH Utrecht, The Netherlands DRUG TARGETING: FACT OR FICTION ? RECEPTOR MEDIATED ENDOCYTOSIS AS A POTENTIAL MECHANISM FOR TISSUE-SPECIFIC DRUG DELIVERY D.K.F. Meijer An increased drug selectivitv can in principle be obtained by covalently linking of drugs to a blodegradable carrier. The p a r t i c u l a r macromolecu le s h o u l d be s p e c i f i c a l l y r e c o g n i z e d by r e c e p t o r s f o r e n d o c y t o s i s on the c e l l s u r f a c e o f the o rgan or t i s s u e where the d rug i s r e q u i r e d f o r i t s ac t i o n . A l o c a l d rug d e l i v e r y o f p o t e n t i a l l y ve ry t o x i c compounds may not on ly d e c r e a s e u n d e s i r a b l e s i d e e f f e c t s and t o x i c L t y on o t h e r t i s s u e s ( " p a s s i v e t a r g e t i n g " ) , but can a l s o produce a marked i n c r e a s e in po tency of the d rug ( " a c t i v e t a r g e t i n g " ) . The s i m p l i c i t y o f the d rug t a r g e t i n g concep t however i s i n v e r s e l y r e l a t e d to the c o m p l e x i t y in the p r o p e r d e s i g n of t h e r a p e u t i c dosage forms f o r human use . Apar t from p h a r m a c e u t i c a l p rob lems such as chemica l s t a b [ l i t y , p r a c t i c a l r o u t e s of a d m i n i s t r a t i o n and c o s t s o f manuf a c t u r i n g , c h r o n i c t o x i c i t y on the RES sys tem as w e l l as p o s s i b l e i m m u n o g e n i c i t y have to be t aken i n t o a c c o u n t . In a d d i t i o n , the i n t r a c e l l u l a r f a t e o f the d r u g c a r r i e r complex not on ly in normal but a l s o in h e t e r o g e n o u s p a t h o l o g i c a l t i s s u e s h o u l d be c l e a r l y d e f i n e d b e f o r e r a t i o n a l c l a i m s of improved d rug s p e c i f i c i t y can be made. Examples a re h e p a t o t r o p i c c a r r i e r s y s t e m s f o r a n t [ v i r a l a g e n t s d i r e c t e d to v i r a l h e p a t i t i s , a n t i p r o t o z o a l compounds ( m a l a r i a e t c . ) , a n t [ n e o p l a s t i c a g e n t s , enzymes f o r t r e a t m e n t of g e n e t i c enzyme d e f ~ q l e n c i e s , exogenous c h o l e s t e r o l to m a n i p u l a t e c h o l e s t e r o l s y n t h e s i s , d i p h t e r i a t o x i n to i n h i b i t p r o t e i n s y n t h e s i s , f o l i n i c a c i d to " r e s c u e " h e p a t o c y t e s from gener a l t o x i c i t y of m e t h o t r e x a t e and p robes f o r t e s t i n g h e p a t i c l y sosoma l f u n c t i o n . I n t e r e s t i n g l y some of t h e s e d e s i g n s can be e x t r a n o l a t e d to o t h e r t i s s u e s and may w e l l reach the s t a g e of c l i n i c a l t e s t i n g . I t i s c o n c l u d e d t h a t the r e s e a r c h o f d rug t a r g e t i n g r e q u i r e s a m u l t i d i s c i p l i n a r y c e l l b i o l o g i c a l as w e l l as an i n t e g r a l p h a r m a c e u t i c a l approach to g u a r a n t e e p r a c t i c a l s o l u t i o n s to the ve ry complex p rob lems in t h i s a r e a . Dept. of PharmacoloRy and P h a r m a c o t h e r a p e u t i c s , S u b f a c u l t y o f Pharmacy, U n i v e r s i t y o f C r o n f n g e n , Ant . D e u s i n g l a a n 2, q713 AW C r o n i n e e n , The N e t h e r l a n d s . MACROMOLECULAR PRODRUGS OF ADRIAMYCIN C.J.T. Hoes W, W.A.R. van Heeswijk*, B. de Grooth § J. Mud +, J. Oreve + and J. FelJen*