32 Drug delivery systems,second edition 10.Maruyama,K.Unezaki,S.,Takahashi,N.,and Iwatsuru, M.,Enhanced de Bioch 111 c149209-216195 on of apolipo ith lipos 31299 112 mand suocuulate drug availability po con arm.Worl ,15,173-175,1998 113.Kedar. E D ski,Y,Braun,E.Emanuel,N.,and Barenholz,Y.,Deliv of cytokines by lipo L Prep ry 114. some targetingn problems ar nd opportunities,Biol.Cell. 115.H kin cific delive ery: cellular and challe nges utical As s Iohn Wile 2748,198 116.Cleland,LG.Robe B.V.Ga nd Allen.T.M.Co d anti-inflan tisol palmit effect in rats compar ared with fre isol.Agents Actions.12.348-352.1982 117.De Silva,M.Hazelman,B.L,Page-Thomas,D.P.,and Wraight,P.,Liposomes in arthritis:a new ach.La cet,1,1320-1322.1979 118.Fehr.K Velvart.M Roos k al Th 0c1e35.2986.1985 119.Fuiiwara.T.Maeta.H.Chida.S.Morita T.Watabe Y and Abe.T.Artificial in hvaline me disea 2,Lancet,.8159,55-59,1980. 120.Talsma,Han Crommelin D.JA Liposomes as drug delivery systems Pharm.Tech.Nover ber1992.16.52-58. 121.Price C.L and Horton,Local Liposome Delivery:An Overlooked Application CRC Press,Boca Raton,FL,1994. 122.Hua L.Ed.lournal of Linos e Research.Marcel Dekker.New York.1993 123.Klimchak,RJ.and Lenk,RPScale-up of liposome products,Biopharmacology 18.1988. 124.H ng.MS.Lim.SI.Oh.YK et al.pH ser circulating lipos 51-58,2002 125.Harigai,T.Kondo,M.,Isozaki,M.,et al.,Preferential binding of polyethylene 126.Kunisawa,J.and Mayumi,T.,Application of novel drug delivery system fusogenic li nes for cancer ther y,Gan To Kagaku Ryoho,5,577-583,2001. 127.Kaneda,Y.,Virosomes:evolution of the lipc somes as a targeted drug delivery. Adu.Dr1 tg Del.Reu.43.197-_205.2000 128.Paavola,A.,Kilpelanien,I.,and Ylirussi,J.,Controlled-release injectable lipo somal gel of ibuprofen for epidural analgesia,Int.J.Pharm.,199,85-93,2000 129.Lewanski,C.R.and Stewart,S.,Pegylated liposomal adriamycin:a review of current and future applications,Pharm.Sci.Technol.Today,1461-534712 473477.1999. 130.Nagarsenker,M.S.,Londhe,V.Y.,and Nadkarni,G.D.,Preparation and eval- uation of liposomal formulations of tropicamide for ocular delivery,Int.J. Pharm,190,63-71,1999
32 Drug delivery systems, second edition 110. Maruyama, K., Unezaki, S., Takahashi, N., and Iwatsuru, M., Enhanced delivery of doxorubicin to tumor, Biochim. Biophys. Acta, 1149, 209–216, 1993. 111. Lundberg, B., Hong, K., and Papahadjopoulos, D., Conjugation of apolipoprotein B with liposomes, Biochim. Biophys. Acta, 305–312, 1993. 112. Kadir, F., Intramuscular and subcutaneous drug delivery: encapsulation in liposomes and other methods to manipulate drug availability, Pharm. World Sci., 15, 173–175, 1993. 113. Kedar, E., Rutkowski, Y., Braun, E., Emanuel, N., and Barenholz, Y., Delivery of cytokines by liposomes. I. Preparation and characterization of interleukin-2 encapsulated in long-circulating sterically stabilized liposomes, J. Immunother., 16(1), 47–59, 1994. 114. Posete, G., Liposome targeting in vivo: problems and opportunities, Biol. Cell., 47, 19–38, 1983. 115. Hopkins, C.R., Site-specific delivery: cellular opportunities and challenges. In Site-Specific Drug Delivery, Tomlinson, E. and Davis, S.S., Eds., Cell Biology Medical and Pharmaceutical Aspects, John Wiley & Sons, Chichester, 27–48, 1986. 116. Cleland, L.G., Roberts, B.V., Garrett, R., and Allen, T.M., Cortisol palmitate liposomes: enhanced anti-inflammatory effect in rats compared with free cortisol, Agents Actions, 12, 348–352, 1982. 117. De Silva, M., Hazelman, B.L., Page-Thomas, D.P., and Wraight, P., Liposomes in arthritis: a new approach, Lancet, 1, 1320–1322, 1979. 118. Fehr, K., Velvart, M., Roos, K., et al., Therapiewoche, 35, 2986, 1985. 119. Fujiwara, T., Maeta, H., Chida, S., Morita, T., Watabe, Y., and Abe, T., Artificial surfactant therapy in hyaline membrane disease, Lancet, 8159, 55–59, 1980. 120. Talsma, H. and Crommelin, D.J.A., Liposomes as drug delivery systems, Pharm. Tech., November 1992, 16, 52–58. 121. Price, C.I. and Horton, J., Local Liposome Delivery: An Overlooked Application, CRC Press, Boca Raton, FL, 1994. 122. Huang, L., Ed., Journal of Liposome Research, Marcel Dekker, New York, 1993. 123. Klimchak, R.J. and Lenk, R.P., Scale-up of liposome products, Biopharmacology, 18, 1988. 124. Hong, M.S., Lim, S.J., Oh, Y.K., et al., pH sensitive, serum-stable and long circulating liposomes as a new drug delivery system, J. Pharm. Pharmacol., 54, 51–58, 2002. 125. Harigai, T., Kondo, M., Isozaki, M., et al., Preferential binding of polyethylene glycol-coated liposomes containing a novel cationic lipid: TRX 20 to human subendothelial via chondroitin sulfate, Pharm. Res., 18, 1284–1290, 2001. 126. Kunisawa, J. and Mayumi, T., Application of novel drug delivery system: fusogenic liposomes for cancer therapy, Gan To Kagaku Ryoho, 5, 577–583, 2001. 127. Kaneda, Y., Virosomes: evolution of the liposomes as a targeted drug delivery. Adv. Drug Del. Rev., 43, 197–205, 2000. 128. Paavola, A., Kilpelanien, I., and Ylirussi, J., Controlled-release injectable liposomal gel of ibuprofen for epidural analgesia, Int. J. Pharm., 199, 85–93, 2000. 129. Lewanski, C.R. and Stewart, S., Pegylated liposomal adriamycin: a review of current and future applications, Pharm. Sci. Technol. Today, 1461–5347, 12, 473–477, 1999. 130. Nagarsenker, M.S., Londhe, V.Y., and Nadkarni, G.D., Preparation and evaluation of liposomal formulations of tropicamide for ocular delivery, Int. J. Pharm., 190, 63–71, 1999
Chapter one:Site-specific drug delivery using liposomes as carriers 33 131.Adlakha-Hutcheon.G.Bally.M.B.Shew.C.R.et al.Controlled destabiliza tion of a liposomal drug delivery system enhances mitoxantrone antitumor activity,Nat.Biotechnol 8,775-779,1999. 132.Fresta,M.,Panico,A.M.,Bucolo,C.,et al.,Characterization and in vivo ocular absorption of liposome-encapsulated acyclovir,I.Pharm.Pharmacol.,5, 565576.1999 133.Babincova,M.,Targeted and controlled release of drugs using magnetolipo- somes,Cesk Slov.Farm.,48,27-29,1999. 134.Suntres,ZE.and Shek,P.N.,Liposomes promote pulmonary glucocorticoid delivery,J.Drug Target,6,175-182,1998. 135.Nagae,L,Koy nagi,Y.,Ito,S.,et al.,Liposome drug delivery system for murine neuroblastoma,I.Pediatr.Surg,33,1521-1525,1998. 136.Desormeux,A.and Bergeron,M.G.,Liposomes as a drug delivery system:a strategic approach for the treatment of HIV infection,J.Drug Target,6,1-15 1998 137.Vora,B.,Khopade,A.J.,and Jain,N.K.,Proniosome-based transdermal deliv ery of levonorgestrel for effective contraception,I.Control Release,54,149-165 1998. 138.Cortesi,R.,Espisoto,E.,Maietti,A.,et al.,Production and antiproliferative activity of liposomes containing the antitumor drug chromomycin A3,J Microencapsul.,4,465-472,1998. 139.Arakawa,A.,Ishiguro,S.,Ohki,K.,et al.,Preparation of liposome-encapsu- lating adenosine triphosphate,Tohoku J.Exp.Med.,184,39-47,1998. 140.Murahashi,N.,Ishihara,H.,and Sakagami,M.,Synthesis and application of neoglycolipids for liposome modification,Biol.Pharm.Bull.,6,704-707 1997 141.Murahashi,N.,Ishihara,H.,Sasaki,A.,et al.,Hepatic accumulation of glutam- ic-acid-branched neogalactosyllipid modified liposomes,Biol.Pharm.Bull.,3, 259-266,1997. 142.D'Souza,S.A.,Ray,J.Pandey,S.,et al.,Absorption of ciprofloxacin and norfloxacin when administered as niosome-encapsulated inclusion complex- es,J.Pharma.Pharmacol,49,145-149,1997 143.Huwyler,J,Wu,D.,and Pardridgr,W.M.,Brain drug delivery of small mol- ecules using immunoliposomes,Proc.Nat.Acad.Sci.USA,93,14164-14169 1996. 144.Gonzalez-Rothi,R.J.,Suarez,S.,and Hochhaus,G.,Pulmonary targeting of liposomal triamcinolone acetonide phosphate,Pharmt.Res.13,1699-1703 1996. 145.Banerjee,G.,Nandi,G.,Mahato,S.B.,et al.,Drug delivery system:targeting of pentamidines to specific sites using sugar-grafted liposomes,Antimicrob. Chemother.,38,145- 50,1996 146.Chelvi,P.T.,Jain,S.K.,and Ralhan,R.,Heat-mediated selective delivery of liposome-associated melphalan in murine melanoma,Melanoma Res.,5, 321-326.1995 147.Grimaldi,S.,Giuliani,A.,Giuliani,A.,et al.,Engineered liposomes and vi- rosomes for delivery of macromolecules,Res.Virol.,164,289-293,1995. 148.Sharan,R.N.,Alam,A.,and Chakravorty,S.,2-Mercaptopropionylglycine affords enhanced radioprotection after a liposome encapsulation,J.Radiat Res.,36,31-37,1995
Chapter one: Site-specific drug delivery using liposomes as carriers 33 131. Adlakha-Hutcheon, G., Bally, M.B., Shew, C.R., et al., Controlled destabilization of a liposomal drug delivery system enhances mitoxantrone antitumor activity, Nat. Biotechnol., 8, 775–779, 1999. 132. Fresta, M., Panico, A.M., Bucolo, C., et al., Characterization and in vivo ocular absorption of liposome-encapsulated acyclovir, J. Pharm. Pharmacol., 5, 565–576, 1999. 133. Babincova, M., Targeted and controlled release of drugs using magnetoliposomes, Cesk Slov. Farm., 48, 27–29, 1999. 134. Suntres, Z.E. and Shek, P.N., Liposomes promote pulmonary glucocorticoid delivery, J. Drug Target, 6, 175–182, 1998. 135. Nagae, I., Koyanagi, Y., Ito, S., et al., Liposome drug delivery system for murine neuroblastoma, J. Pediatr. Surg, 33, 1521–1525, 1998. 136. Desormeux, A. and Bergeron, M.G., Liposomes as a drug delivery system: a strategic approach for the treatment of HIV infection, J. Drug Target, 6, 1–15, 1998. 137. Vora, B., Khopade, A.J., and Jain, N.K., Proniosome-based transdermal delivery of levonorgestrel for effective contraception, J. Control Release, 54, 149–165, 1998. 138. Cortesi, R., Espisoto, E., Maietti, A., et al., Production and antiproliferative activity of liposomes containing the antitumor drug chromomycin A3, J. Microencapsul., 4, 465–472, 1998. 139. Arakawa, A., Ishiguro, S., Ohki, K., et al., Preparation of liposome-encapsulating adenosine triphosphate, Tohoku J. Exp. Med., 184, 39–47, 1998. 140. Murahashi, N., Ishihara, H., and Sakagami, M., Synthesis and application of neoglycolipids for liposome modification, Biol. Pharm. Bull., 6, 704–707, 1997. 141. Murahashi, N., Ishihara, H., Sasaki, A., et al., Hepatic accumulation of glutamic-acid-branched neogalactosyllipid modified liposomes, Biol. Pharm. Bull., 3, 259–266, 1997. 142. D’Souza, S.A., Ray, J., Pandey, S., et al., Absorption of ciprofloxacin and norfloxacin when administered as niosome-encapsulated inclusion complexes, J. Pharma. Pharmacol., 49, 145–149, 1997. 143. Huwyler, J., Wu, D., and Pardridgr, W.M., Brain drug delivery of small molecules using immunoliposomes, Proc. Nat. Acad. Sci. USA, 93, 14164–14169, 1996. 144. Gonzalez-Rothi, R.J., Suarez, S., and Hochhaus, G., Pulmonary targeting of liposomal triamcinolone acetonide phosphate, Pharm. Res., 13, 1699–1703, 1996. 145. Banerjee, G., Nandi, G., Mahato, S.B., et al., Drug delivery system: targeting of pentamidines to specific sites using sugar-grafted liposomes, J. Antimicrob. Chemother., 38, 145–150, 1996. 146. Chelvi, P.T., Jain, S.K., and Ralhan, R., Heat-mediated selective delivery of liposome-associated melphalan in murine melanoma, Melanoma Res., 5, 321–326, 1995. 147. Grimaldi, S., Giuliani, A., Giuliani, A., et al., Engineered liposomes and virosomes for delivery of macromolecules, Res. Virol., 164, 289–293, 1995. 148. Sharan, R.N., Alam, A., and Chakravorty, S., 2-Mercaptopropionylglycine affords enhanced radioprotection after a liposome encapsulation, J. Radiat. Res., 36, 31–37, 1995
34 Drug delivery systems,second edition gaphennmmmengaRC 149.Daoud,S.S,Fetouh,M.I,and Giovanella,B.C,Antitumor effect of lipo 150 s.Hansbroug ,J.F.Zapata-Si ent,R,etal Soft-tissue infection re 151 37-47.1995 nd release 152 Takeuchi,H.Kojima,H.Yama rith a modified take ir 5-205,200 153.Alving VR Koulchin,V.an GM.L antigens:induction of arriers of peptide ntibodies and cy 154.Hong.Ms Lim,S.J and Lee,M.K.Prolor d blood circulation of metho Drug Deli,8231-237,2001 s in the treatr ent of hepatic metastasary investigation by autoradiography analysis. 156.Fre 157.Chrai,S.S.Murari,R.,and Ahmad,A.,Liposomes:a review,Pharm.Tech,26 28-342002
34 Drug delivery systems, second edition 149. Daoud, S.S., Fetouh, M.I., and Giovanella, B.C., Antitumor effect of liposome-incorporated camptothecin in human malignant xenografts, Anticancer Drugs, 6, 83–93, 1995. 150. Grayson, L.S., Hansbrough, J.F., Zapata-Sirvent, R., et al., Soft-tissue infection prophylaxis with gentamicin encapsulated in multivesicular liposomes: results from a prospective randomized trial, Crit. Care Med., 23, 84–91, 1995. 151. Sehgal, S. and Rogers, J.A., Polymer-coated liposomes: improved liposome stability and release of cytosine arabinoside (Ara-C), J. Microencapsul., 12, 37–47, 1995. 152. Takeuchi, H., Kojima, H., Yamamoto, H., et al., Polymer coating of liposomes with a modified polyvinyl alcohol and their systemic circulation and RES uptake in rats, J. Controlled Rel., 68, 195–205, 2000. 153. Alving, V.R., Koulchin, V., and Glenn, G.M., Liposomes as carriers of peptide antigens: induction of antibodies and cytotoxic T lymphocytes to conjugated and unconjugated peptides, Immunol. Rev., 145, 5–31, 1995. 154. Hong, M.S., Lim, S.J., and Lee, M.K., Prolonged blood circulation of methotrexate by modulation of liposomal composition, Drug Deliv., 8. 231–237, 2001. 155. Pavanetto, F., Perugini, P., et al., Boron-loaded liposomes in the treatment of hepatic metastases: preliminary investigation by autoradiography analysis., Drug Deliv., 7, 97–103, 2000. 156. Freund, O., Biodistribution and gastrointestinal drug delivery of new lipidic multilamellar vesicles, Drug Deliv., 8, 239–244, 2001. 157. Chrai, S.S., Murari, R., and Ahmad, A., Liposomes: a review, Pharm. Tech., 26, 28–34, 2002
chapter two Site-specific drug delivery utilizing monoclonal antibodies* Contents I.Introduction Chemistry 35 36 Polyclonals vs.monoclonals 36 Conjugation of antibodies. II.Production of monoclonal antibodies. .37 A Continuously proliferating cell lines .38 B. Human-human hybridomas. 38 Large -scale production. 38 III.Drug-monoclonal antibody conjugates for drug targeting. A. Principles B. Drug antibody bonding.39 In vitro and in vivo testing. .40 IV.Recent studies with monoclonal antibodies. .43 A Highlights of current research .43 Conclusion and basis for future trends. References. 54 I. Introduction At the beginning of this century,Paul Ehrlich reported the discovery of antibodies.Since that time,many investigators have done extensive work using a wide variety of a molecul in imr radio medic in employed a method of somatic-cell hybridization in order to successfully generate a +Adapted from Ranade,V.V.,Drug delivery systems.2.Site-specific drug delivery utilizing monoclonal antibodies,.Clin.Pharmacol.29,873,1989.With permission of the .Clin.Pharma- col.,and J.B.Lippincott Publishing Company,Philadelphia,PA. 必
35 chapter two Site-specific drug delivery utilizing monoclonal antibodies* Contents I. Introduction .35 A. Chemistry .36 B. Polyclonals vs. monoclonals.36 C. Conjugation of antibodies.36 II. Production of monoclonal antibodies .37 A. Continuously proliferating cell lines .38 B. Human–human hybridomas .38 C. Large-scale production.38 III. Drug-monoclonal antibody conjugates for drug targeting.39 A. Principles .39 B. Drug antibody bonding .39 C. In vitro and in vivo testing .40 IV. Recent studies with monoclonal antibodies.43 A. Highlights of current research .43 V. Conclusion and basis for future trends.52 References.54 I. Introduction At the beginning of this century, Paul Ehrlich reported the discovery of antibodies.1 Since that time, many investigators have done extensive work using a wide variety of antibody molecules in immunocytochemistry, radioimmunoassay, and clinical medicine. In 1976, Kohler and Milstein employed a method of somatic-cell hybridization in order to successfully generate a * Adapted from Ranade, V.V., Drug delivery systems. 2. Site-specific drug delivery utilizing monoclonal antibodies, J. Clin. Pharmacol., 29, 873, 1989. With permission of the J. Clin. Pharmacol., and J.B. Lippincott Publishing Company, Philadelphia, PA
36 Drug delivery systems,second edition continuous"hybridoma"cell line capable of producing monoclonal antibody (MAb)of a defined specificity.2Subsequently,several MAbs have exhibited specificity for target sites.It is this property of MAbs that makes them excel- lent candidates as carriers of therapeutic agents for delivery to specific sites.3 A Chemistry Antibodies are complex proteins,consisting of multiple polypeptide chains that contain a variety of reactive chemical groups,such as amino,carboxyl hydroxyl,and sulfhydryl.Functionally,MAbs p ossess a molecular polarity based on the joini of an ntig fragmer t (Fab)to a ment-fixing fragment(F p sible for specific ant gen binding,whereas the Fc fragment binds to effector cells,fixes comple- ments,and elicits other in vivo biological responses. In order to obtain a MAb suitable for the treatment of human disease,it snecessary to maintain both the physical and functional properties of the antibody t ughout the steps of production, nd mod- ification.Antibody modification,performed to increase theoretical efficacy,can consist of conjugation of the protein to the following:radionuclides (e.g.,311 and iIn),chemotherapeutic drugs (e.g.,methotrexate and vinblastine),and polypeptide toxins(e.g.,ricin A chain and polkweed antiviral protein [PAPD) Polyclonals vs.monoclonals Antibodies can be heterogeneous with respect to size,charge,antigen spec- ificity,and affinity.These factors may be significant when antibodies are used as a drug delivery stem,either alone or when conjugated.For example some ant ibody mol may be egraded rapidly and creted while rmay have longer hal-ivEarier used polyconal anti bodies for drug targeting.5s However,polyclonals contain an inherent defi- ciency due to lack of specificity that is further compounded by the fact that reproducibility within polyclonal antisera was not always obtained.In view of these problems,res earchers continued to focus on developing MAbs with their ndant ing d specifici Polyclonal antibodies may offer potential advantages in drug delivery such as recognition of more than one specific location at a given target site However,this can also be achieved by using mixtures of MAbs of desired specificity.A wide range of animal species can be used to produce polyclonal antibodies.which is a distinct advantage.At the esent time,production of MAbs is predominantly limited to mice,rats,and,to some extent,humans. Conjugation of antibodies Drug targeting and delivery using antibodies has been most useful in the field of chemotherapy because this is an area of research in which th re is the greatest need for target-site specificity.Anticancer drugs,in particula r,ofter display high toxicity,and they frequently have a low therapeutic index
36 Drug delivery systems, second edition continuous “hybridoma” cell line capable of producing monoclonal antibody (MAb) of a defined specificity.2 Subsequently, several MAbs have exhibited specificity for target sites. It is this property of MAbs that makes them excellent candidates as carriers of therapeutic agents for delivery to specific sites.3,4 A. Chemistry Antibodies are complex proteins, consisting of multiple polypeptide chains that contain a variety of reactive chemical groups, such as amino, carboxyl, hydroxyl, and sulfhydryl. Functionally, MAbs possess a molecular polarity based on the joining of an antigen-binding fragment (Fab) to a complement-fixing fragment (Fc). The Fab fragment is responsible for specific antigen binding, whereas the Fc fragment binds to effector cells, fixes complements, and elicits other in vivo biological responses. In order to obtain a MAb suitable for the treatment of human disease, it is necessary to maintain both the physical and functional properties of the antibody throughout the steps of production, isolation, purification, and modification. Antibody modification, performed to increase theoretical efficacy, can consist of conjugation of the protein to the following: radionuclides (e.g.,131I and 111In), chemotherapeutic drugs (e.g., methotrexate and vinblastine), and polypeptide toxins (e.g., ricin A chain and polkweed antiviral protein [PAP]). B. Polyclonals vs. monoclonals Antibodies can be heterogeneous with respect to size, charge, antigen specificity, and affinity. These factors may be significant when antibodies are used as a drug delivery system, either alone or when conjugated. For example, some antibody molecules may be degraded rapidly and excreted while others may have longer half-lives.3–5 Earlier researchers used polyclonal antibodies for drug targeting.6–8 However, polyclonals contain an inherent defi- ciency due to lack of specificity that is further compounded by the fact that reproducibility within polyclonal antisera was not always obtained. In view of these problems, researchers continued to focus on developing MAbs with their attendant increased specificity.9 Polyclonal antibodies may offer potential advantages in drug delivery, such as recognition of more than one specific location at a given target site. However, this can also be achieved by using mixtures of MAbs of desired specificity. A wide range of animal species can be used to produce polyclonal antibodies, which is a distinct advantage. At the present time, production of MAbs is predominantly limited to mice, rats, and, to some extent, humans.10 C. Conjugation of antibodies Drug targeting and delivery using antibodies has been most useful in the field of chemotherapy11,12 because this is an area of research in which there is the greatest need for target-site specificity. Anticancer drugs, in particular, often display high toxicity, and they frequently have a low therapeutic index.2,13,14