Influence of the structure of drug moieties on the in vitro efficacy of HPMA copolymer-geldanamycin derivative conjugates

• Published in: Pharmaceutical research 2002-02, Vol.19 (2), p.115-123
• Main Authors: KASUYA, Yuji, LU, Zheng-Rong, KOPECKOVA, Pavla, TABIBI, S. Esmail, KOPECEK, Jindrich
• Format: Article
• Language: English
• Subjects: Acrylamides - chemistry; Antibiotics, Antineoplastic - chemistry; Antibiotics, Antineoplastic - pharmacology; Antineoplastic agents; Benzoquinones; Biological and medical sciences; Cancer; Cathepsin B - antagonists & inhibitors; Chemical Phenomena; Chemistry, Physical; Chemotherapy; Copolymers; Cysteine Proteinase Inhibitors - chemistry; Cysteine Proteinase Inhibitors - pharmacology; Cytotoxicity; Drug delivery systems; Drug Stability; Drugs; Excipients; Female; General pharmacology; Humans; Hydrolysis; Lactams, Macrocyclic; Lysosomes - enzymology; Medical sciences; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - pathology; Ovaries; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Quinones - chemistry; Quinones - pharmacology; Solubility; Tumor Cells, Cultured
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1023/A:1014216712820

To optimize the structure of geldanamycin (GDM) derivative moieties attached to N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers via an enzymatically degradable spacer. HPMA copolymers containing different AR-GDM (AR = 3-aminopropyl (AP), 6-aminohexyl (AH), and 3-amino-2-hydroxypropyl AP(OH)) were synthesized and characterized. Their cytotoxicity towards the A2780 human ovarian carcinoma cells was evaluated. The cytotoxic efficacy of HPMA copolymer-AR-GDM conjugates depended on the structure of AR-GDM. Particularly, HPMA copolymer-bound AH-GDM, which possessed the longest substituent at the 17-position, demonstrated the highest efficacy among the polymer-bound GDM derivatives; however the activity of free AH-GDM was lower than that of the other free AR-GDMs. The relative increase of the activity of macromolecular AH-GDM when compared to AP-GDM or AP(OH)-GDM correlated with the enhanced recognition of AH-GDM terminated oligopeptide side-chains by the active site of the lysosomal enzyme, cathepsin B. Drug stability and further stabilization upon binding to HPMA copolymer also contributed to the observed phenomena. AH-GDM was found to be a suitable GDM derivative for the design of a drug delivery system based on HPMA copolymers and enzymatically-degradable spacers.