Doxorubicin-HPMA

For cancer therapy, the well estabhshed N(-2-hydroxypropyl)methacrylamide (HMPA) polymers have been extensively studied. PKl, a 28-kDa HPMA copolymer containing doxorubicin (Figure 1.3) is now in clinical testing [15]. Other drugs that have been incorporated... 

Figure 1.3. Structure of PKl (HPMA copolymer doxorubicin), a 28-kDa polymeric carrier-drug conjugate investigated for its anti-tumour activity in a phase I clinical study. Adapted from reference [15].

B16 melanoma, Walker sarcoma, and M5076 forming liver metastasis have been used in the preclinical evaluation of HPMA copolymer-adriamydn conjugates [36]. Other tumors useful for secondary screening are MS-2 sarcoma, NMU-1 murine lung adenocarcinoma, and murine adenocarcinoma Colon 26. These have been used by Zunino et al. [147] to determine the activity of poly (carboxylic acid) immobilized anthracyclines. Mice inoculated intramuscularly with Lewis lung carcinoma have been used by Pratesi et al. [215] to assess the effect of a poly-L-aspartic acid/doxorubicin conjugate. 

Ten mice per group were immunized every 3rd day (five times). On the 3rd and 6th days after the last treatment the mice were exsanguinated and the sera stored at - 70 °C. Numbers represent an average of ten individually tested sera. P = HPMA copolymer backbone ADR = adriamycin (doxorubicin) gal = galac-tosamine bound via the NH2 group... 

P = HPMA copolymer backbone ADR = adriamycin (doxorubicin) gal = galactosamine bound via the NH2 group... 

Duncan R, Coatsworth JK, Burtles S. Preclinical toxicology of a novel polymeric antitumour agent HPMA copolymer-doxorubicin (PK1). Hum Exp Toxicol 1998 17(2) 93—104. 

Luo, Y., et al. 2002. Targeted delivery of doxorubicin by HPMA copolymer-hyaluronan bioconjugates. Pharm Res 19 396. 

Etrych, T., Jelinkova, M., Rihova, B., and Ulbrich, K. New HPMA copolymers containing doxorubicin bound via pH-sensitive linkage Synthesis and preliminary in vitro and in vivo biological properties. J. Contr. Rel. 73(1) 89-102. 2001. 

Jelinkova, M., Strohalm, J., Plocova, D., et al. Targeting of human and mouse T-lym-phocytes by monoclonal antibody-HPMA copolymer-doxorubicin conjugates directed against different T-cell surface antigens. J. Cont. Rel. 52 253-270, 1998. 

Figure 5.5 Chemical structure of a doxorubicin-N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer conjugate...

The bulk of the conjugate consists of unmodified HPMA units (x in Figure 5.5) which comprise about 90% of the carrier while the remaining units (y) are derivatized with doxorubicin. A tetrapeptide spacer... 

C. Young, A.M. Hesslewood, S. Morrison, R. Preliminary clinical study of the distribution of HPMA copolymers bearing doxorubicin and galactosamine. Journal of Controlled Release 1999, 57, 281-290. 

Figure 3 HPMA copolymer-anticancer conjugates. Panel (a) HPMA copol3mier-doxorubicin (PKl, FCE28068) panel (b) HPMAcopolymer-doxorubicin-galactosamine (PK2, FCE28069) panel (c) HPMAcopoly-mer-paclitaxel panel (d) HPMA copolymer-camptothecin.

HPMA copolymer-drug conjugation greatly increases the solubilify of hydrophobic drugs, e.g., doxorubicin solubility increases > 10-fold in FCE28068, but despite this high... 

Figure 11 Facingpage) HPMA copolymer-anticancer conjugates demonstrate improved targeting of chemotherapy to an sc B16F10 solid tumor models in vivo. The data shown represent the time-dependent accumulation of (a) PKl and free doxorubicin and (b) HPMA copolymer-platinate. (From Refs. 90,188.)...

Figure 12 Uptake of HPMA copolymer-doxorubicin (PKl) at 1 h in tumors of different sizes. Panel (a) shows tumor accumulation in sc B16F10 tumors in terms of % dose per tumor. As the tumors increased in size, uptake increased. Panel (b) shows B16F10 tumor uptake in terms of % dose per gram of tumor. As size increases uptake in these terms reduces. Panel (c) shows uptake (% dose per gram of tumor) in MAC 15A colon xenografts of different sizes. In this case non-size dependence of uptake is seen. (From Ref. 194.)...

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