The intracellular drug delivery and anti tumor activity of doxorubicin loaded poly(gamma-benzyl L-glutamate)-b-hyaluronan polymersomes.

Abstract

We have investigated the intracellular delivery of doxorubicin (DOX) loaded poly(gamma-benzyl L-glutamate)-block-hyaluronan (PBLG-b-HYA) based polymersomes (PolyDOX) in high (MCF-7) and low (U87) CD44 expressing cancer cell models. DOX was successfully loaded into polymersomes using nanoprecipitation method and in vitro drug release pattern were achieved at pH 5.5 and 7.4 up to 10 days. Block copolymer vesicles without loaded DOX were non cytotoxic in both cells at concentration 150-650 microg/mL. Flow cytometry data suggested successful uptake of PolyDOX in cells and high accumulation was found in MCF-7 than U87 cells. Microscopy imagings revealed that in MCF-7 cells PolyDOX was more in cytoplasm and free DOX in nuclei, whereas in U87 cells free DOX was also found in the cytoplasm. Cytotoxicity of the drug was concentration and exposure time dependent. In addition, PolyDOX significantly enhanced reactive oxygen species (ROS) level in both cells. PolyDOX also suppressed growth of breast tumor on female Sprague-Dawley (SD) rats as compared to phosphate buffer saline pH 7.4 (PBS) control group. In addition reduced level of serum enzymes (LDH and CPK) by PolyDOX formulation indicated less cardiotoxicity of DOX after loading in polymersomes. Results suggest that intracellular delivery of PolyDOX was depended on the CD44 expression level in cells due to presence of hyaluronic acid on the surface of polymersomes, and could be used as a self-targeting drug delivery cargo in over-expressed CD44 glycoprotein cells of breast cancer.

• Authors: Kamal K Upadhyay, Anant N Bhatt, Anil K Mishra, Bilikere S Dwarakanath, Sanyog Jain, Christophe Schatz, Jean-François Le Meins, Abdullah Farooque, Godugu Chandraiah, Amit K Jain, Ambikanandan Misra, Sébastien Lecommandoux
• Journal: Biomaterials (Biomaterials) Vol. 31 Issue 10 Pg. 2882-92 (Apr 2010) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 20053435 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: 2009 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Cardiotoxins
• Hyaluronan Receptors
• Reactive Oxygen Species
• poly(gamma-benzyl glutamate)-b-hyaluronan
• poly-gamma-benzyl-L-glutamate
• Polyglutamic Acid
• Doxorubicin
• Hyaluronic Acid
• L-Lactate Dehydrogenase
• Creatine Kinase

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cardiotoxins (pharmacology)
• Cell Death (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Creatine Kinase (blood)
• Doxorubicin (administration & dosage, pharmacology)
• Drug Delivery Systems
• Female
• Flow Cytometry
• Humans
• Hyaluronan Receptors (metabolism)
• Hyaluronic Acid (analogs & derivatives, pharmacology)
• Hydrogen-Ion Concentration (drug effects)
• Intracellular Space (drug effects, metabolism)
• Kaplan-Meier Estimate
• L-Lactate Dehydrogenase (blood)
• Microscopy, Electron, Transmission
• Microscopy, Fluorescence
• Polyglutamic Acid (analogs & derivatives, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Reactive Oxygen Species (metabolism)