NOVEL HYDROXYL TERMINATED DENDRIMERS AS POTENTIAL DRUG CARRIERS: SUSTAINED RELEASE, HEMOLYSIS AND CYTOTOXICITY STUDY
Objective: Potential of novel hydroxyl terminated dendrimer generations G1(OH)8, G2(OH)32 and G3(OH)128 as solubility enhancers of model drug ketoprofen was evaluated. G3(OH)128 dendrimer was further explored as the novel carrier for sustained release of ketoprofen. Cytotoxicity and hemolytic potential of G3(OH)128 dendrimer were studied to evaluate toxicity of dendrimer.
Methods: Higuchi and Connors method was employed to evaluate improved solubility of ketoprofen at different pH and dendrimer generation. Ketoprofen was loaded into G3(OH)128 dendrimer by inclusion complex method. Ketoprofen loaded dendrimer was characterized by Flourier Transform infrared spectroscopy. Sustained release of ketoprofen from ketoprofen loaded dendrimers was studied and compared to that of free ketoprofen. Cytotoxicity of dendrimers on A-549 cell lines were studied by MTT assay technique. Hemolytic potential of G3 dendrimer was also studied.
Results: Solubility of practically insoluble ketoprofen was improved up to 0.77-4.89 mg/ml by dendrimer generations. Solubility of ketoprofen was increased with increase in pH, concentrationand generation number of dendrimer. Ketoprofen was released relatively slowly from ketoprofen loaded dendrimer compared to free ketoprofen. Cytotoxicity and hemolytic assay revealed that dendrimers were less toxic compared to PAMAM dendrimers.
Conclusion: Improved solubility of ketoprofen by dendrimer generations, its slow release from G3(OH)128 dendrimer and cytotoxicity and hemolytic assay showed dendrimers have potential as drug carriers.
Keywords: Triazine Based Dendrimer, Sustained Release, Cytotoxicity, Hemolysis, Ketoprofen, Encapsulation.
2. Yalkowsky S. Techniques of solubilization of drugs. New York: Marcel Dekker; 1981.
3. Karkan M, Li L, Muller RH. Overcoming the challenge of poor drug solubility. Pharm Eng 2012;32:1-7.
4. Gupta U, Aghashe HB, Asthana A, Jain NK. Dendrimers: novel polymeric nanoarchitectures for solubility enhancement. Biomacromol 2006;7:649-58.
5. Dhandapani NV, Thapa A, Sandip G, Shrestha A, Shrestha N, Bhattarai RS. Liposomes as novel drug delivery system. Int J Res Pharm Sci 2013:187-93.
6. Fung LK, Saltzman WM. Polymeric implants for cancer chemotherapy. Adv Drug Deliv Rev 1997;26:209-30.
7. Tomalia DA. Birth of a new macromolecular architecture: dendrimers as quantized building blocks for nanoscale synthetic organic chemistry. Al Acta 2004;37:39-57.
8. Liu M, Kono K, Frechet JMJ. Water-soluble dendritic unimolecular micelles: Their potential as drug delivery agents. J Controlled Release 2000;65:121-31.
9. Maeda H, Fang J, Inutsuka T, Kitamoto Y. Vascular permeability enhancement in solid tumor: various factors, mechanisms involved and its implications. Int Immunopharmacol 2003;3:319-28.
10. Svenson S, Tomalia DA. Dendrimers in biomedical applications-reflections on the field. Adv Drug Delivery Rev 2012;64:102-15.
11. Lim J, Simanek EE. Triazine dendrimers as drug delivery systems: From synthesis to therapy. Adv Drug Delivery Rev 2012;64:826-35.
12. Gajjar D, Patel R, Patel H, Patel PM. Designing, characterization, and thermal behavior of triazine-based dendrimers. J Polym Eng 2015;35(1):41-52.
13. Gajjar D, Patel R, Patel H, Patel PM. Designing of triazine based dendrimer and its application in removal of heavy metal ions from water. Chem Sci Trans 2014;3(3):897-908.
14. Gajjar D, Patel R, Patel H, Patel PM. Desalin water treat removal of heavy metal ions from water by hydroxyl terminated Triazine-based Dendrimer. Desalin Water Treat Published Ahead of the Print; 2015.
15. Patel R, Patel H, Gajjar D, Patel PM. Removal of Cu2+, Ni2+and Zn2+metal ions from water by hydroxyl terminated s-triazine based dendrimer. Malay Polym J 2014;9(2):70-7.
16. Gajjar D, Patel R, Patel H, Patel PM. Triazine based dendrimer as solubility enhancers of ketoprofen: effect of concentration, pH and Generationâ€. Int J Pharm Pharm Sci 2014;6:357-61.
17. Patel R, Patel H, Gajjar D, Patel PM. Enhanced solubility of non-steroidal anti-inflammatory drugs by hydroxyl terminated s-triazine based dendrimers. Asian J Pharm Clin Res 2014;7(2):156-61.
18. Padilla De JesÃºs OL, Ihre HR, Gagne L, FrÃ©chet JMJ, Szoka FC. Polyester dendritic systems for drug delivery applications: In vitro and In vivo evaluation. Bioconjugate Chem 2002;13:453-61.
19. Higuchi T, Connors A. Phase-solubility techniques. In: Advances in Analytical Chemistry and Instrumentation, New York, John Wiley; 1965.
20. Kolhe P, Misra E, Kannan RM, Kannan S, Lieh-Lai M. Drug complexation, in vitro release and cellular entry of dendrimers and hyperbranched polymers. Int J Pharm 2003;259:143â€“60.
21. Jain S, Kaur A, Puri R, Utreja P, Jain A, Bhide M, et al. Poly propyl ether imine (PETIM) dendrimer: A novel non-toxic dendrimer for sustained drug delivery. Eur J Med Chem 2010;45:4997-5005.
22. Bansal KK, Kakde D, Gupta U, Jain NK. Development and characterization of triazine based dendrimers for delivery of antitumor agent. J Nanosci Nanotechnol 2010;10:8395-04.
23. Duncan R, Izzo L. Dendrimer biocompatibility and toxicity. Adv Drug Delivery Rev 2005;57:2215-37.
24. Domanski DM, Klajnert B, Bryszewska M. Influence of PAMAM dendrimers on human red blood cells. Bioelectrochem 2004;63:189-91.
25. Na M, Yiyun C, Tongwen X, Yang D, Xiaomin W, et al. Dendrimers as potential drug carriers. Part II. Prolonged delivery of ketoprofen by in vitro and in vivo studies. Eur J Med Chem 2006;41:670-4.
26. Shao N, Su Y, Hu J, Zhang J, Zhang H, Cheng Y. Comparison of generation 3 polyamidoamine dendrimer and generation 4 polypropylenimine dendrimer on drug loading, complex structure, release behavior, and cytotoxicity. Int J Nanomed 2011;6:3361-72.