Synthesis, Characterization and Antitumor Activity of Macromolecular Prodrugs of Adriamycin

Heeswijk, Wolfgang A.R. van; Stoffer, T.; Eenink, M.J.D.; Potman, W.; Vijgh, W.J.F. van der; Poort, Joost; Pinedo, H.M.; Lelieveld, P.; Feijén, Jan

doi:10.1007/978-1-4613-2745-5_6

Cited by 8 publications

(3 citation statements)

References 44 publications

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“…At this stage we can confirm, using the analysis reported earlier, HPLC analysis of the preparations, and the measured activities of daunomycin-HPMA conjugates against L1210 and CCRF cells in vitro are not due to the presence of free drug in the conjugate. This contrasts with observations of Van Heeswijk et al, (1984), who prepared polyglutamic acid-adriamycin conjugates, tested using an L1210 clonogenic assay and reported cytotoxic activity. Since these conjugates contained 0.5-2% weight free adriamycin, their cytotoxicity was largely ascribed to free adriamycin.…”

Section: Discussioncontrasting

confidence: 99%

Anticancer agents coupled to N-(2-hydroxypropyl)methacrylamide copolymers. I. Evaluation of daunomycin and puromycin conjugates in vitro

Duncan¹,

Kopečkova-Rejmanová²,

Strohalm³

et al. 1987

Br J Cancer

166

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Summary During recent years N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers have been developed as targetable drug carriers. These soluble synthetic polymers are internalized by cells by pinocytosis and they can be tailor-made to include peptidyl side-chains degradable intracellularly by specific lysosomal enzymes. Thus they provide the opportunity fo achieve controlled intracellular delivery of anticancer agents. The anthracycline antibiotic daunomycin, and protein synthesis inhibitor puromycin, were bound to HPMA copolymers via several different peptide side-chains, including Gly-Gly, Gly-Phe-Leu-Gly and Gly-Phe-PheLeu. Incubation of polymer-drug conjugates with isolated lysosomal enzymes (either a mixture of rat liver lysosomal enzymes or purified thiol-dependent lysosomal proteinases, cathepsins L and B) showed that significant release of drug occurred over 20h, more than 20% of daunomycin and more than 80% of puromycin being liberated. To test their pharmacological activity conjugates were incubated with either the mouse leukaemia L1210, or the human lymphoblastoid leukaemia CCRF in vitro. The conjugates tested were all less effective than free daunomycin, but they showed differential toxicity against L1210 depending on the aminoacid sequence of their drug-polymer linkage. Inclusion of fucosylamine-terminating side-chains into the HPMA copolymer structure increased the affinity of conjugates for the L1210 cell membrane and resulted in increased toxicity. In contrast HPMA-daunomycin conjugates with or without fucosylamine affected CCRF cells equally, but this cell line was more sensitive than the mouse leukaemia to both free and polymer-bound daunomycin. Incubation of L1210 cells in polymer-bound daunomycin for 72h, followed by plating cells out in low density in drug-free medium, showed that a concentration of polymer-bound drug (184,ugml-1) could be selected to achieve a cytotoxic effect.

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Section: Discussioncontrasting

confidence: 99%

Anticancer agents coupled to N-(2-hydroxypropyl)methacrylamide copolymers. I. Evaluation of daunomycin and puromycin conjugates in vitro

Duncan¹,

Kopečkova-Rejmanová²,

Strohalm³

et al. 1987

Br J Cancer

166

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“…DOX was conjugated to HA (100 kDa) by means of three different linking chemistries: (1) direct conjugation via DMTMM chemistry, forming an amide bond and (2) through a flexible, hydrophobic, and long adipic dihydrazide or (3) short hydrazide linker (see Scheme 1). In the latter two strategies, the linking chemistry allowed the generation of a pH-responsive hydrazine, possibly through 13 DOX ketone [32,33].…”

Section: Synthesis and Characterization Of Ha-dox Conjugatesmentioning

confidence: 99%

Design of Bio-Responsive Hyaluronic Acid–Doxorubicin Conjugates for the Local Treatment of Glioblastoma

Malfanti¹,

Catania²,

Degros³

et al. 2022

Pharmaceutics

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Glioblastoma is an unmet clinical need. Local treatment strategies offer advantages, such as the possibility to bypass the blood–brain barrier, achieving high drug concentrations at the glioblastoma site, and consequently reducing systemic toxicity. In this study, we evaluated the feasibility of using hyaluronic acid (HA) for the local treatment of glioblastoma. HA was conjugated to doxorubicin (DOX) with distinct bio-responsive linkers (direct amide conjugation HA-NH-DOX), direct hydrazone conjugation (HA-Hz-DOX), and adipic hydrazone (HA-AdpHz-DOX). All HA-DOX conjugates displayed a small size (less than 30 nm), suitable for brain diffusion. HA-Hz-DOX showed the best performance in killing GBM cells in both 2D and 3D in vitro models and displayed superior activity in a subcutaneous GL261 tumor model in vivo compared to free DOX and other HA-DOX conjugates. Altogether, these results demonstrate the feasibility of HA as a polymeric platform for the local treatment of glioblastoma and the importance of rationally designing conjugates.

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“…The final products of degradation were tetrapeptide fragments. VAN HEESWIJK et al (1984) conjugated adriamycin to poly-a-Lglutamic acid y-carboxyl groups via an amide bond. These conjugates were designed as macromolecular prodrugs for the selective release of free drug in tumor cells having elevated levIes of y-glutamyl transferase (GT).…”

Section: Polyamino Acidsmentioning

confidence: 99%

Soluble Polymers as Targetable Drug Carriers

Krinick¹,

Kopeček²

1991

Targeted Drug Delivery

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Synthesis, Characterization and Antitumor Activity of Macromolecular Prodrugs of Adriamycin

Cited by 8 publications

References 44 publications

Anticancer agents coupled to N-(2-hydroxypropyl)methacrylamide copolymers. I. Evaluation of daunomycin and puromycin conjugates in vitro

Anticancer agents coupled to N-(2-hydroxypropyl)methacrylamide copolymers. I. Evaluation of daunomycin and puromycin conjugates in vitro

Design of Bio-Responsive Hyaluronic Acid–Doxorubicin Conjugates for the Local Treatment of Glioblastoma

Soluble Polymers as Targetable Drug Carriers

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