The structure-dependent toxicity, pharmacokinetics and anti-tumour activity of HPMA copolymer conjugates in the treatment of solid tumours and leukaemia
Language English Country Netherlands Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
26708020
DOI
10.1016/j.jconrel.2015.12.023
PII: S0168-3659(15)30275-3
Knihovny.cz E-resources
- Keywords
- Anti-tumour activity, Doxorubicin, HPMA, Structure, Toxicity,
- MeSH
- Acrylamides chemistry pharmacokinetics therapeutic use toxicity MeSH
- Dendrimers chemistry pharmacokinetics therapeutic use toxicity MeSH
- Doxorubicin chemistry pharmacokinetics therapeutic use toxicity MeSH
- Liver drug effects pathology MeSH
- Bone Marrow drug effects pathology MeSH
- Maximum Tolerated Dose MeSH
- Molecular Weight MeSH
- Mice, Inbred BALB C MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Neoplasms blood drug therapy metabolism MeSH
- Drug Carriers * chemistry pharmacokinetics therapeutic use toxicity MeSH
- Antibiotics, Antineoplastic * chemistry pharmacokinetics therapeutic use toxicity MeSH
- Spleen drug effects pathology MeSH
- Intestinal Mucosa metabolism MeSH
- Structure-Activity Relationship MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Acrylamides MeSH
- Dendrimers MeSH
- Doxorubicin MeSH
- N-(2-hydroxypropyl)methacrylamide co-polymer-doxorubicin conjugate MeSH Browser
- Drug Carriers * MeSH
- PAMAM Starburst MeSH Browser
- Antibiotics, Antineoplastic * MeSH
Polymer drug carriers that are based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers have been widely used in the development and synthesis of high-molecular-weight (HMW) drug delivery systems for cancer therapy. In this study, we compared linear (Mw ~27kDa, Rh ~4nm) and non-degradable star (Mw ~250kDa, Rh ~13nm) HPMA copolymer conjugates bearing anthracycline antibiotic doxorubicin (DOX) bound via pH-sensitive hydrazone bond. We determined the in vitro and in vivo toxicity of both conjugates and their maximum tolerated dose (MTD). We also compared their anti-tumour activity in mouse B-cell leukaemia (BCL1) and a mouse T-cell lymphoma (EL4) model. We found that MTD was higher for the linear conjugate (85mgDOX/kg) and lower for the star conjugate (22.5mgDOX/kg). An evaluation of the intestinal barrier integrity using FITC-dextran as a gut permeability tracer proved that no pathology was caused by the MTD of either conjugate. However, free DOX showed some damage to the gut barrier. The therapy of BCL1 leukaemia by both of the polymeric conjugates using the MTD or its fraction (i.e., equitoxic dosage) showed better results in the case of the star conjugate. On the other hand, treatment of EL4 lymphoma seemed to be more efficient when the linear conjugate was used. We suppose that the anti-cancer treatment of solid tumours and leukaemias requires different types of drug conjugates. We hypothesise that the most suitable HPMA copolymer-DOX conjugate for the treatment of solid tumours should have an HMW structure with increased Rh that would be stable for three to four days after the conjugate administration and then rapidly disintegrate in the short polymer chains, which are excretable from the body by glomerular filtration. On the other hand, the treatment of leukaemia requires a drug conjugate with a long circulation half-life. This would provide an active drug, whilst slowly degrading to excretable fragments.
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