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Published on: October 28, 2015
Chlorin e6 Conjugated Methoxy-Poly(Ethylene Glycol)-Poly(D,L-Lactide) Glutathione Sensitive Micelles for Photodynamic
Preeti Kumari1, Milan Paul1, Himanshu Bhatt1
1Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Medchal, Hyderabad, Telangana, 500078, India.
Purpose:
In this study, we developed a polymeric micellar system for glutathione-mediated intracellular delivery of a photosensitizer, chlorin e6 (Ce6) by synthesizing an amphiphilic polymer, methoxy-poly(ethylene glycol)-poly(D,L-lactide)-disulfide-Ce6 (mPEG-PLA-S-S-Ce6), which self-assembled in aqueous environment to form micelles.
Methods:
The polymer-drug conjugate was characterized by NMR. The singlet oxygen (2O1) generation and in vitro release of Ce6 micelles were evaluated. Further, glutathione-mediated intracellular drug delivery was assessed in human alveolar adenocarcinoma cells (A549), mouse mammary carcinoma cells (4 T1) and 3D A549 spheroids.
Results:
The micellar system protected Ce6 from aggregation leading to improved 2O1 generation compared to free Ce6. Due to the availability of glutathione, the disulfide bonds in the micelles were cleaved resulting in rapid release of Ce6 evident from the in vitro study. The Ce6 micelles displayed quicker drug release in presence of glutathione monoester (GSH-OEt) pre-treated A549 and 4 T1 cells compared to without pre-treated cells. In vitro phototoxicity of micelles displayed enhanced toxicity in 10 mM GSH-OEt pre-treated A549 and 4 T1 cells compared to untreated cells. As anticipated, Ce6 micelles showed lower drug release in presence of 0.1 mM of buthionine sulfoximine (BSO) pretreated A549 and 4 T1 cells exhibiting lower phototoxicity. Further, A549 3D spheroids treated with Ce6 micelles showed significant inhibition in growth, enhanced phototoxicity, and cellular apoptosis in comparison to free Ce6.
Conclusion:
The above results showed that the developed strategy could be effective in improving the PDT efficacy of Ce6, and the developed polymeric micellar system could be utilized as a PDT regimen for cancer.
