Back to Search
Start Over
Ligand-directed reduction-sensitive shell-sheddable biodegradable micelles actively deliver doxorubicin into the nuclei of target cancer cells.
- Source :
-
Biomacromolecules [Biomacromolecules] 2013 Oct 14; Vol. 14 (10), pp. 3723-30. Date of Electronic Publication: 2013 Sep 16. - Publication Year :
- 2013
-
Abstract
- The therapeutic performance of biodegradable micellar drugs is far from optimal due to existing challenges like poor tumor cell uptake and intracellular drug release. Here, we report on ligand-directed reduction-sensitive shell-sheddable biodegradable micelles based on poly(ethylene glycol)-poly(ε-caprolactone) (PEG-PCL) copolymer actively delivering doxorubicin (DOX) into the nuclei of target cancer cells, inducing superb in vitro antitumor effects. The micelles were constructed from PEG-SS-PCL and galactose-PEG-PCL (Gal-PEG-PCL) block copolymers, in which Gal-PEG-PCL was designed with a longer PEG than that in PEG-SS-PCL (6.0 vs 5.0 kDa) to fully expose Gal ligands onto the surface of micelles for effective targeting to hepatocellular carcinoma cells. PEG-SS-PCL combining with 10 or 20 wt % of Gal-PEG-PCL formed uniform micelles with average sizes of 56.1 and 58.2 nm (denoted as PEG-SS-PCL/Gal10 and PEG-SS-PCL/Gal20, respectively). The in vitro release studies showed that about 81.1 and 75.0% DOX was released in 12 h from PEG-SS-PCL/Gal10 and PEG-SS-PCL/Gal20 micelles under a reducing condition containing 10 mM dithiothreitol (DTT). In contrast, minimal DOX release (<12%) was observed for PEG-SS-PCL/Gal10 and PEG-SS-PCL/Gal20 micelles under nonreducing conditions as well as for reduction-insensitive Gal-PEG-PCL and PEG-PCL/Gal20 micelles in the presence of 10 mM DTT. MTT assays in HeLa and HepG2 cells showed that DOX-loaded PEG-SS-PCL/Gal20 micelles exhibited apparent targetability and significantly enhanced antitumor efficacy toward asialoglycoprotein receptor (ASGP-R)-overexpressing HepG2 cells with a particularly low half maximal inhibitory concentration (IC50) of 1.58 μg DOX equiv/mL, which was comparable to free DOX and approximately six times lower than that for nontargeting PEG-SS-PCL counterparts under otherwise the same conditions. Interestingly, confocal microscopy observations using FITC-labeled PEG-SS-PCL/Gal20 micelles showed that DOX was efficiently delivered and released into the nuclei of HepG2 cells in 8 h. Flow cytometry revealed that cellular DOX level in HepG2 cells treated with DOX-loaded PEG-SS-PCL/Gal20 micelles was much greater than that with reduction-insensitive PEG-PCL/Gal20 and nontargeting PEG-SS-PCL controls, signifying the importance of combining shell-shedding and active targeting. Ligand-directed, reduction-sensitive, shell-sheddable, and biodegradable micelles have emerged as a versatile and potent platform for targeted cancer chemotherapy.
- Subjects :
- Antineoplastic Agents administration & dosage
Antineoplastic Agents metabolism
Antineoplastic Agents pharmacology
Carcinoma, Hepatocellular drug therapy
Carcinoma, Hepatocellular metabolism
Cell Proliferation drug effects
Cell Survival drug effects
Dose-Response Relationship, Drug
Doxorubicin administration & dosage
Drug Screening Assays, Antitumor
Ethylene Glycols administration & dosage
Ethylene Glycols chemistry
Hep G2 Cells
Humans
Ligands
Liver Neoplasms drug therapy
Liver Neoplasms metabolism
Models, Biological
Molecular Structure
Oxidation-Reduction
Particle Size
Polyesters administration & dosage
Polyesters chemistry
Structure-Activity Relationship
Surface Properties
Carcinoma, Hepatocellular pathology
Cell Nucleus metabolism
Doxorubicin metabolism
Doxorubicin pharmacology
Drug Delivery Systems
Liver Neoplasms pathology
Micelles
Subjects
Details
- Language :
- English
- ISSN :
- 1526-4602
- Volume :
- 14
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Biomacromolecules
- Publication Type :
- Academic Journal
- Accession number :
- 23998942
- Full Text :
- https://doi.org/10.1021/bm401098w