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Drug Delivery Letters

Author(s): Ashish K. Parashar, Preeti Patel, Arun K. Gupta, Neetesh K. Jain and Balak Das Kurmi*

DOI: 10.2174/2210303109666190401231920

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Synthesis, Characterization and in vivo Evaluation of PEGylated PPI Dendrimer for Safe and Prolonged Delivery of Insulin

Page: [248 - 263] Pages: 16

  • * (Excluding Mailing and Handling)

Abstract

Objective: The present study was aimed at developing and exploring the use of PEGylated Poly (propyleneimine) dendrimers for the delivery of an anti-diabetic drug, insulin.

Methods: For this study, 4.0G PPI dendrimer was synthesized by successive Michael addition and exhaustive amidation reactions, using ethylenediamine as the core and acrylonitrile as the propagating agent. Two different activated PEG moieties were employed for PEGylation of PPI dendrimers. Various physicochemical and physiological parameters UV, IR, NMR, TEM, DSC, drug entrapment, drug release, hemolytic toxicity and blood glucose level studies of both PEGylated and non- PEGylated dendritic systems were determined and compared.

Results: PEGylation of PPI dendrimers caused increased solubilization of insulin in the dendritic framework as well as in PEG layers, reduced drug release and hemolytic toxicity as well as increased therapeutic efficacy with reduced side effects of insulin. These systems were found to be suitable for sustained delivery of insulin by in vitro and blood glucose-level studies in albino rats, without producing any significant hematological disturbances.

Conclusion: Thus, surface modification of PPI dendrimers with PEG molecules has been found to be a suitable approach to utilize it as a safe and effective nano-carrier for drug delivery.

Keywords: Dendrimer (s), PEGylation, insulin, drug delivery systems, disease state(s), diabetes.

Graphical Abstract

[1]
Agashe, H.B.; Dutta, T.; Garg, M.; Jain, N.K. Investigations on the toxicological profile of functionalized fifth-generation poly (propylene imine) dendrimer. J. Pharm. Pharmacol., 2006, 58(11), 1491-1498.
[2]
Kurmi, B.D.; Gajbhiye, V.; Kayat, J.; Jain, N.K. Lactoferrin-conjugated dendritic nanoconstructs for lung targeting of methotrexate. J. Pharm. Sci., 2011, 100(6), 2311-2320.
[3]
Morales-Espinoza, E.G.; Sanchez-Montes, K.E.; Klimova, E.; Klimova, T.; Lijanova, I.V.; Maldonado, J.L.; Ramos-Ortiz, G.; Hernandez-Ortega, S.; Martinez-Garcia, M. Dendrimers containing ferrocene and porphyrin moieties: Synthesis and cubic non-linear optical behavior. Molecules, 2010, 15(4), 2564-2575.
[4]
Singh, P.; Moll, F., III; Lin, S.H.; Ferzli, C.; Yu, K.S.; Koski, R.K.; Saul, R.G.; Cronin, P. Starburst dendrimers: Enhanced performance and flexibility for immunoassays. Clin. Chem., 1994, 40(9), 1845-1849.
[5]
Baytekin, B.; Baytekin, H.T.; Hahn, U.; Reckien, W.; Kirchner, B.; Schalley, C.A. Dendrimer disassembly in the gas phase: A cascade fragmentation reaction of Frechet dendrons. Chemistry, 2009, 15(29), 7139-7149.
[6]
Frechet, J.M. Functional polymers and dendrimers: Reactivity, molecular architecture, and interfacial energy. Science, 1994, 263(5154), 1710-1715.
[7]
Tambe, P.; Kumar, P.; Paknikar, K.M.; Gajbhiye, V. Smart triblock dendritic unimolecular micelles as pioneering nanomaterials: Advancement pertaining to architecture and biomedical applications. J. Control. Release, 2019, 299, 64-89.
[8]
Svenson, S.; Chauhan, A.S. Dendrimers for enhanced drug solubilization. Nanomedicine (Lond.), 2008, 3(5), 679-702.
[9]
Kumar, P.V.; Agashe, H.; Dutta, T.; Jain, N.K. PEGylated dendritic architecture for development of a prolonged drug delivery system for an antitubercular drug. Curr. Drug Deliv., 2007, 4(1), 11-19.
[10]
Svenson, S.; Tomalia, D.A. Dendrimers in biomedical applications--reflections on the field. Adv. Drug Deliv. Rev., 2005, 57(15), 2106-2129.
[11]
Kurmi, B.D.; Kayat, J.; Gajbhiye, V.; Tekade, R.K.; Jain, N.K. Micro- and nanocarrier-mediated lung targeting. Expert Opin. Drug Deliv., 2010, 7(7), 781-794.
[12]
Taratula, O.; Garbuzenko, O.B.; Kirkpatrick, P.; Pandya, I.; Savla, R.; Pozharov, V.P.; He, H.; Minko, T. Surface-engineered targeted PPI dendrimer for efficient intracellular and intratumoral siRNA delivery. J. Control. Release, 2009, 140(3), 284-293.
[13]
Jain, K.; Verma, A.K.; Mishra, P.R.; Jain, N.K. Surface-engineered dendrimeric nanoconjugates for macrophage-targeted delivery of amphotericin B: formulation development and in vitro and in vivo evaluation. Antimicrob. Agents Chemother., 2015, 59(5), 2479-2487.
[14]
Tekade, R.K.; Dutta, T.; Tyagi, A.; Bharti, A.C.; Das, B.C.; Jain, N.K. Surface-engineered dendrimers for dual drug delivery: A receptor up-regulation and enhanced cancer targeting strategy. J. Drug Target., 2008, 16(10), 758-772.
[15]
Bhadra, D.; Bhadra, S.; Jain, P.; Jain, N.K. Pegnology: A review of PEG-ylated systems. Pharmazie, 2002, 57(1), 5-29.
[16]
Acton, A.L.; Fante, C.; Flatley, B.; Burattini, S.; Hamley, I.W.; Wang, Z.; Greco, F.; Hayes, W. Janus PEG-based dendrimers for use in combination therapy: Controlled multi-drug loading and sequential release. Biomacromolecules, 2013, 14(2), 564-574.
[17]
Kojima, C.; Kono, K.; Maruyama, K.; Takagishi, T. Synthesis of polyamidoamine dendrimers having poly(ethylene glycol) grafts and their ability to encapsulate anticancer drugs. Bioconjug. Chem., 2000, 11(6), 910-917.
[18]
Pikal, M.J.; Rigsbee, D.R. The stability of insulin in crystalline and amorphous solids: Observation of greater stability for the amorphous form. Pharm. Res., 1997, 14(10), 1379-1387.
[19]
Fineberg, S.E.; Galloway, J.A.; Fineberg, N.S.; Rathbun, M.J.; Hufferd, S. Immunogenicity of recombinant DNA human insulin. Diabetologia, 1983, 25(6), 465-469.
[20]
Hinds, K.D.; Kim, S.W. Effects of PEG conjugation on insulin properties. Adv. Drug Deliv. Rev., 2002, 54(4), 505-530.
[21]
Liu, M.; Kono, K.; Frechet, J.M. Water-soluble dendritic unimolecular micelles: Their potential as drug delivery agents. J. Control. Release, 2000, 65(1-2), 121-131.
[22]
Domanski, D.M.; Klajnert, B.; Bryszewska, M. Influence of PAMAM dendrimers on human red blood cells. Bioelectrochemistry, 2004, 63(1-2), 189-191.