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HPMA copolymer-phospholipase C and dextrin-phospholipase A2 as model triggers for polymer enzyme liposome therapy (PELT).
- Source :
-
Journal of drug targeting [J Drug Target] 2017 Nov - Dec; Vol. 25 (9-10), pp. 818-828. Date of Electronic Publication: 2017 Aug 10. - Publication Year :
- 2017
-
Abstract
- 'Polymer Enzyme Liposome Therapy' (PELT) is a two-step anticancer approach in which a liposomal drug and polymer-phospholipase conjugate are administered sequentially to target the tumour interstitium by the enhanced permeability and retention effect, and trigger rapid, local, drug release. To date, however, the concept has only been described theoretically. We synthesised two polymer conjugates of phospholipase C (PLC) and A2 (PLA2) and evaluated their ability to trigger anthracycline release from the clinically used liposomes, Caelyx <superscript>®</superscript> and DaunoXome <superscript>®</superscript> . N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymer-PLC and a dextrin-PLA2 were synthesised and their enzymatic activity characterised. Doxorubicin release from polyethyleneglycol-coated (PEGylated) Caelyx <superscript>®</superscript> was relatively slow (<20%, 60 min), whereas daunomycin was rapidly released from non-PEGylated DaunoXome <superscript>®</superscript> (∼87%) by both enzymes. Incubation with dextrin-PLA2 triggered significantly less daunomycin release than HPMA copolymer-PLC, but when dextrin-PLA2 was pre-incubated with α-amylase, the rate of daunomycin release increased. DaunoXome <superscript>®'</superscript> s diameter increased in the presence of PLA2, while Caelyx <superscript>®</superscript> 's diameter was unaffected by free or conjugated PLA2. Dextrin-PLA2 potentiated the cytotoxicity of DaunoXome <superscript>®</superscript> to MCF-7 cells to a greater extent than free PLA2, while combining dextrin-PLA2 with Caelyx <superscript>®</superscript> resulted in antagonism, even in the presence of α-amylase, presumably due to steric hindrance by PEG. Our findings suggest that in vivo studies to evaluate PELT combinations should be further evaluated.
- Subjects :
- Cell Survival drug effects
Cell Survival physiology
Dextrins administration & dosage
Dose-Response Relationship, Drug
Doxorubicin administration & dosage
Doxorubicin metabolism
Humans
Liposomes
MCF-7 Cells
Methacrylates administration & dosage
Phospholipases A2 administration & dosage
Polyethylene Glycols administration & dosage
Polyethylene Glycols metabolism
Polymers administration & dosage
Type C Phospholipases administration & dosage
Dextrins metabolism
Doxorubicin analogs & derivatives
Methacrylates metabolism
Phospholipases A2 metabolism
Polymers metabolism
Type C Phospholipases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1029-2330
- Volume :
- 25
- Issue :
- 9-10
- Database :
- MEDLINE
- Journal :
- Journal of drug targeting
- Publication Type :
- Academic Journal
- Accession number :
- 28728446
- Full Text :
- https://doi.org/10.1080/1061186X.2017.1358726