Biological properties of adriamycin bound to biodegradable polymeric carriers
Hoes, C.J.T. and Grootoonk, J. and Duncan, R. and Hume, I.C. and Bhakoo, M. and Bouma, J.M.W. and Feijen, J. (1993) Biological properties of adriamycin bound to biodegradable polymeric carriers. Journal of Controlled Release, 23 (1). pp. 37-54. ISSN 0168-3659
|Abstract:||Three different conjugates having adriamycin (ADR) bound to the side chain carboxyl groups of high-molecular weight poly (¿--glutamic acid) (PGA) either directly or by interpolation of GlyGly and GlyGlyGlyLeu spacers, respectively, were compared with respect to immunogenicity and cytotoxicity in mice as well as release of drug by lysosomal enzymes. The cytotoxic efficacy of a single i.p. dose of each conjugate (5 mg ADR-equiv./kg) against L1210 leukemia cells implanted i.p. in DBA2 mice was studied by monitoring the survival time, the body weight and the number of long-term survivors (LTS). PGA-GlyGlyGlyLeu-ADR and PGA-GlyGly-ADR significantly enhanced the mean survival time (MST) of treated animals compared with the untreated control group (T/C 148¿149%) as did free ADR (T/C 147%). The tetrapeptide-spacer containing conjugate effected the presence of LTS at day 50 (2/5) as did free ADR (1/5).
The secondary antibody response of the drug conjugates elicited in A/J mice after repeated dosage (125 ¿g/mouse) at day 0, 14 and 28 was evaluated at day 35 using the ELISA technique. IgG titers varied from a very low value (PGA-GlyGlyGlyLeu-ADR) to moderately high levels (PGA-ADR, PGA-GlyGly-ADR) which are 2¿3 orders of magnitude below that obtained for the strong immunogen bovine IgG. The data suggest that certain parts on the surface of the conjugates are immunogenic.
The release of extractable low-molecular weight products from the conjugates mediated by lysosomal enzymes was analyzed using reversed-phase HPLC. The release profile of ADR as well as Gly-ADR, Leu-ADR or GlyLeu-ADR was determined. The total amount of ADR released after 77 h was 3.6% for PGA-GlyGlyGly-Leu-ADR, 1.0% for PGA-GlyGly-ADR and 0.5% for PGA-ADR. With all conjugates unidentified products were produced.
It is proposed that the mechanism of action of the polymeric conjugates under in vivo conditions may be due to pinocytic capture followed by lysosomal degradation with release of ADR.
|Copyright:||© 1993 Elsevier Science|
Science and Technology (TNW)
|Link to this item:||http://purl.utwente.nl/publications/9687|
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