PAMAM dendrimers: Destined for success or doomed to fail? Plain and modified PAMAM dendrimers in the context of biomedical applications

Journal of Pharmaceutical Sciences

Volumn 104, Issue 1, 2015, Pages 2-14

  Labieniec Watala, Magdalena ^a   Watala, Cezary ^b  

^a UNIVERSITY OF LODZ   (Poland)

^b MEDICAL UNIVERSITY OF LODZ   (Poland)

Author keywords

Biomaterials; Nanoparticles; Nanotechnology; Nonenzymatic glycosylation; PAMAM dendrimers; Polymers; Surface chemistry; Toxicity

Indexed keywords

DENDRIMER; LYSINE; POLYAMIDOAMINE; POLYMER; BIOMATERIAL; NANOPARTICLE; PAMAM STARBURST; POLYAMINE;

BIOCOMPATIBILITY; BIODEGRADATION; BIOLOGICAL ACTIVITY; BIOMEDICINE; CONJUGATION; CYTOTOXICITY; DRUG BIOAVAILABILITY; DRUG DELIVERY SYSTEM; ENCAPSULATION; GLYCOSYLATION; HUMAN; NANOTECHNOLOGY; NONHUMAN; PHYSICAL CHEMISTRY; REVIEW; STATIC ELECTRICITY; ADVERSE EFFECTS; ANIMAL; CHEMISTRY; ECONOMICS; SURFACE PROPERTY; TRENDS;

ANIMALS; BIOCOMPATIBLE MATERIALS; DENDRIMERS; DRUG DELIVERY SYSTEMS; HUMANS; NANOPARTICLES; NANOTECHNOLOGY; POLYAMINES; SURFACE PROPERTIES;

EID: 84919800402     PISSN: 00223549     EISSN: 15206017     Source Type: Journal    
DOI: 10.1002/jps.24222     Document Type: Review

References (96)

1. Patel HN, Patel PM. 2013. Dendrimer applications-A review. Int J Pharm Bio Sci 4:P454-P463.
2. Syed IA, Rao YM. 2012. Dendrimers based drug delivery systems. Res J Pharm Toxicol 5:307-316.
3. Rajasekhar D, Liao P-C. 2012. Patents and the development on polymer based nanomaterial (PAMAM dendrimer) for biomedical applications. Recent Patent Biomed Eng 5:159-174.
4. Karolczak K, Rozalska S, Wieczorek M, Labieniec-Watala M, Watala C. 2012. Poly (amido) amine dendrimers generation 4.0 (PAMAM G4) reduce blood hyperglycaemia and restore impaired blood-brain barrier permeability in streptozotocin diabetes in rats. Int J Pharm 436:508-518.
5. Labieniec M, Ulicna O, Vancova O, Glowacki R, Sebekova K, Bald E, Gabryelak T, Watala C. 2008. PAMAM G4 dendrimers lower high glucose but do not improve reduced survival in diabetic rats. Int J Pharm 364:142-149.
6. Labieniec M, Watala C. 2009. PAMAMdendrimers-Diverse biomedical applications. Facts and unresolved questions. Centr Eur J Biol 4:434-451.
7. Labieniec M, Watala C. 2010. Use of poly (amido) amine dendrimers in prevention of early non-enzymatic modifications of biomacromolecules. Biochimie 92:1296-1305.
8. Tomalia DA, Baker H, Baker JR, Dewald J, Hall M, Kallos G, Martin S, Roeck J, Ryder J, Smith P. 1984. New class of polymers: STARBURST-dendritic macromolecules. Polymer J 17:117-132.
9. Cheng YY, Man N, Xu TW, Fu RQ, Wang XY, Wang XM, Wen LP. 2007. Transdermal delivery of nonsteroidal anti-inflammatory drugs mediated by polyamidoamine (PAMAM) dendrimers. J Pharm Sci 96:595-602.
10. Kesharwani P, Jain K, Jain NK. 2014. Dendrimer as nanocarrier for drug delivery. Prog Polym Sci 39:268-307.
11. Pourianazar NT, Mutlu P, Gunduz U. 2014. Bioapplications of (polyamidoamine) PAMAM dendrimers in nanomedicine. J Nanopart Res 16:23-42.
12. Svenson S, Tomalia D. 2012. Dendrimers in biomedical applications-Reflections on the field. Adv Drug Deliv Rev 64:102-115.
13. Dobrovolskaia MA, Patri AK, Simak J, Hall JB, Semberova J, Paoli Lacerda SH, McNeil SE. 2012. Nanoparticle size and surface charge determine effects of PAMAM dendrimers on human platelets in vitro. Mol Pharm 9:382-393.
14. Jones CF, Campbell RA, Franks Z, Gibson CC, Thiagarajan G, Vieira-de-Abreu A, Sukavaneshvar S, Mohammad SF, Li DY, Ghandehari H, Weyrich AS, Brooks BD, Grainger DW. 2012. Cationic PAMAM dendrimers disrupt key platelet functions. Mol Pharm 9:1599-1611.
15. Labieniec-Watala M, Karolczak K, Siewiera K, Watala C. 2013. The Janus face of PAMAM dendrimers used to potentially cure nonenzymatic modifications of biomacromolecules in metabolic disorders-A critical review of the pros and cons. Molecules 18:13769-13811.
16. Markowicz-Piasecka M, Luczak E, Chalubinski M, Broncel M, Mikiciuk-Olasik E, Sikora J. 2014. Studies towards biocompatibility of PAMAM dendrimers-Overall hemostasis potential and integrity of the human aortic endothelial barrier. Int J Pharm 473:158-169.
17. Sadekar S, Ghandehari H. 2012. Transepithelial transport and toxicity of PAMAM dendrimers: Implications for oral drug delivery. Adv Drug Deliv Rev 64:571-588.
18. Tatiya PD, Hedaoo RK, Mahulikar PP, Gite VV. 2013. Novel polyurea microcapsules using dendritic functional monomer: Synthesis, characterization, and its use in self-healing and anticorrosive polyurethane coatings. Ind Eng Chem Res 52:1562-1570.
19. Thiagarajan G, Greish K, Ghandehari H. 2013. Charge affects the oral toxicity of poly (amidoamine) dendrimers. Eur J Pharm Biopharm. 84:330-334.
20. Aillon KL, Xie Y, El Gendy N, Berkland CJ, Forrest ML. 2009. Effects of nanomaterial physicochemical properties on in vivo toxicity. Adv Drug Deliv Rev 61:457-466.
21. Borowska K, Wolowiec S, Rubaj A, Glowniak K, Sieniawska E, Radej S. 2012. Effect of polyamidoamine dendrimer G3 and G4 on skin permeation of 8-methoxypsoralene-In vivo study. Int J Pharm 426:280-283.
22. Gupta U, Agashe HB, Asthana A, Jain NK. 2006. A review of in vitro-in vivo investigations on dendrimers: The novel nanoscopic drug carriers. Nanomedicine 2:66-73.
23. Malik N, Wiwattanapatapee R, Klopsch R, Lorenz K, Frey H, Weener JW, Meijer EW, Paulus W, Duncan R. 2000. Dendrimers: Relationship between structure and biocompatibility in vitro, and preliminary studies on the biodistribution of 125I-labelled polyamidoamine dendrimers in vivo. J Control Release 65:133-148.
24. Roberts JC, Bhalgat MK, Zera RT. 1996. Preliminary biological evaluation of polyamidoamine (PAMAM) Starburst dendrimers. J Biomed Mater Res 30:53-65.
25. Nishikawa M, Takakura Y, Hashida M. 1996. Pharmacokinetic evaluation of polymeric carriers. Adv Drug Deliv Rev 21:135-155.
26. Etrych T, Kovar L, Strohalm J, Chytil P, Rihova B, Ulbrich K. 2011. Biodegradable star HPMA polymer-drug conjugates: Biodegradability, distribution and anti-tumor efficacy. J Control Release 154:241-248.
27. Kaminskas LM, Boyd BJ, Porter CJ. 2011. Dendrimer pharmacokinetics: The effect of size, structure and surface characteristics on ADME properties. Nanomedicine (Lond) 6:1063-1084.
28. Kunzmann A, Andersson B, Thurnherr T, Krug H, Scheynius A, Fadeel B. 2011. Toxicology of engineered nanomaterials: Focus on biocompatibility, biodistribution and biodegradation. Biochim Biophys Acta 1810:361-373.
29. Kobayashi H, Kawamoto S, Saga T, Sato N, Hiraga A, Ishimori T, Akita Y, Mamede MH, Konishi J, Togashi K, Brechbiel MW. 2001. Novel liver macromolecular MR contrast agent with a polypropylenimine diaminobutyl dendrimer core: Comparison to the vascular MR contrast agent with the polyamidoamine dendrimer core. Magn Reson Med 46:795-802.
30. Sato N, Kobayashi H, Hiraga A, Saga T, Togashi K, Konishi J, Brechbiel MW. 2001. Pharmacokinetics and enhancement patterns of macromolecular MR contrast agents with various sizes of polyamidoamine dendrimer cores. Magn Reson Med 46:1169-1173.
31. Albertazzi L, Gherardini L, Brondi M, Sulis SS, Bifone A, Pizzorusso T, Ratto GM, Bardi G. 2013. In vivo distribution and toxicity of PAMAM dendrimers in the central nervous system depend on their surface chemistry. Mol Pharm 10:249-260.
32. Thiagarajan G, Sadekar S, Greish K, Ray A, Ghandehari H. 2013. Evidence of oral translocation of anionic G6.5 dendrimers in mice. Mol Pharm 10:988-998.
33. Sunoqrot S, Bugno J, Lantvit D, Burdette JE, Hong S. 2014. Prolonged blood circulation and enhanced tumor accumulation of folatetargeted dendrimer-polymer hybrid nanoparticles. J Control Release 191:115-122.
34. Wiwattanapatapee R, Carreno-Gomez B, Malik N, Duncan R. 2000. Anionic PAMAM dendrimers rapidly cross adult rat intestine in vitro: A potential oral delivery system? Pharm Res 17:991-998.
35. Dong ZQ, Katsumi H, Sakane T, Yamamoto A. 2010. Effects of polyamidoamine (PAMAM) dendrimers on the nasal absorption of poorly absorbable drugs in rats. Int J Pharm 393:244-252.
36. Dong Z, Hamid KA, Gao Y, Lin Y, Katsumi H, Sakane T, Yamamoto A. 2011. Polyamidoamine dendrimers can improve the pulmonary absorption of insulin and calcitonin in rats. J Pharm Sci 100:1866-1878.
37. Dai H, Navath RS, Balakrishnan B, Guru BR, Mishra MK, Romero R, Kannan RM, Kannan S. 2010. Intrinsic targeting of inflammatory cells in the brain by polyamidoamine dendrimers upon subarachnoid administration. Nanomedicine (Lond) 5:1317-1329.
38. Sadekar S, Ray A, Janat-Amsbury M, Peterson CM, Ghandehari H. 2011. Comparative biodistribution of PAMAM dendrimers and HPMA copolymers in ovarian-tumor-bearing mice. Biomacromolecules 12:88-96.
39. Wilbur DS, Pathare PM, Hamlin DK, Buhler KR, Vessella RL. 1998. Biotin reagents for antibody pretargeting. 3. Synthesis, radioiodination, and evaluation of biotinylated starburst dendrimers. Bioconjug Chem 9:813-825.
40. Kukowska-Latallo JF, Candido KA, Cao Z, Nigavekar SS, Majoros IJ, Thomas TP, Balogh LP, Khan MK, Jr Baker JR. 2005. Nanoparticle targeting of anticancer drug improves therapeutic response in animal model of human epithelial cancer. Cancer Res 65:5317-5324.
41. Lesniak WG, Mishra MK, Jyoti A, Balakrishnan B, Zhang F, Nance E, Romero R, Kannan S, Kannan RM. 2013. Biodistribution of fluorescently labeled PAMAM dendrimers in neonatal rabbits: Effect of neuroinflammation. Mol Pharm 10:4560-4571.
42. Yao HR, Veine DM, Zeng ZZ, Fay KS, Staszewski ED, Livant DL. 2010. Increased potency of the PHSCN dendrimer as an inhibitor of human prostate cancer cell invasion, extravasation, and lung colony formation. Clin Exp Metastasis 27:173-184.
43. Chen HT, Neerman MF, Parrish AR, Simanek EE. 2004. Cytotoxicity, hemolysis, and acute in vivo toxicity of dendrimers based on melamine, candidate vehicles for drug delivery. J Am Chem Soc 126:10044-10048.
44. Padilla De Jesus OL, Ihre HR, Gagne L, Frechet JM, Jr Szoka FC. 2002. Polyester dendritic systems for drug delivery applications: In vitro and in vivo evaluation. Bioconjug Chem 13:453-461.
45. Labieniec-Watala M, Siewiera K. 2013. The impact of seasonal fluctuations on rat liver mitochondria response to tested compounds-A comparison between autumn and spring. new insight into collecting and interpretation of experimental data originating from different seasons. CellBio 2:20-30.
46. Labieniec-Watala M, Siewiera K, Jozwiak Z. 2011. Resorcylidene aminoguanidine (RAG) improves cardiac mitochondrial bioenergetics impaired by hyperglycaemia in a model of experimental diabetes. Int J Mol Sci 12:8013-8026.
47. Siewiera K, Labieniec-Watala M. 2012. Ambiguous effect of dendrimer PAMAM G3 on rat heart respiration in a model of an experimental diabetes-Objective causes of laboratory misfortune or unpredictable G3 activity? Int J Pharm 430:258-265.
48. Diaz E, Vazquez N, Fernandez C, Durand D, Lasaga M, Debeljuk L, Diaz B. 2011. Seasonal variations of substance P in the striatum of the female rat are affected by maternal and offspring pinealectomy. Neurosci Lett 492:71-75.
49. Konior A, Klemenska E, Brudek M, Podolecka E, Czarnowska E, Beresewicz A. 2011. Seasonal superoxide overproduction and endothelial activation in guinea-pig heart; seasonal oxidative stress in rats and humans. J Mol Cell Cardiol 50:686-694.
50. Vazquez N, Diaz E, Fernandez C, Jimenez V, Esquifino A, Diaz B. 2007. Seasonal variations of gonadotropins and prolactin in the laboratory rat. Role of maternal pineal gland. Physiol Res 56:79-88.
51. Labieniec M, Ulicna O, Vancova O, Kucharska J, Gabryelak T, Watala C. 2009. Effect of poly (amido) amine (PAMAM) G4 dendrimer on heart and liver mitochondria in an animal model of diabetes. Cell Biol Int 34:89-97.
52. Graham ML, Janecek JL, Kittredge JA, Hering BJ, Schuurman HJ. 2011. The streptozotocin-induced diabetic nude mouse model: Differences between animals from different sources. Comp Med 61:356-360.
53. Jevprasesphant R, Penny J, Jalal R, Attwood D, McKeown NB, D'Emanuele A. 2003. The influence of surface modification on the cytotoxicity of PAMAM dendrimers. Int J Pharm 252:263-266.
54. Pan GF, Lemmouchi Y, Akala EO, Bakare O. 2005. Studies on PEGylated and drug-loaded PAMAM dendrimers. J Bioact Compat Polym 20:113-128.
55. Kim Y, Klutz AM, Jacobson KA. 2008. Systematic investigation of polyamidoamine dendrimers surface-modified with poly (ethylene glycol) for drug delivery applications: Synthesis, characterization, and evaluation of cytotoxicity. Bioconjug Chem 19:1660-1672.
56. Yang H, Lopina ST, DiPersio LP, Schmidt SP. 2008. Stealth dendrimers for drug delivery: Correlation between PEGylation, cytocompatibility, and drug payload. J Mater Sci Mater Med 19:1991-1997.
57. Harris JM, Chess RB. 2003. Effect of pegylation on pharmaceuticals. Nat Rev Drug Discov 2:214-221.
58. Wang W, Xiong W, Wan JL, Sun XH, Xu HB, Yang XL. 2009. The decrease of PAMAM dendrimer-induced cytotoxicity by PEGylation via attenuation of oxidative stress. Nanotechnology 20:105103.
59. Kolhatkar RB, Kitchens KM, Swaan PW, Ghandehari H. 2007. Surface acetylation of polyamidoamine (PAMAM) dendrimers decreases cytotoxicity while maintaining membrane permeability. Bioconjug Chem 18:2054-2060.
60. Waite CL, Sparks SM, Uhrich KE, Roth CM. 2009. Acetylation of PAMAM dendrimers for cellular delivery of siRNA. BMC Biotechnol 9:38.
61. Luo D, Haverstick K, Belcheva N, Han E, Saltzman WM. 2002. Poly (ethylene glycol)-conjugated PAMAM dendrimer for biocompatible, high-efficiency DNA delivery. Macromolecules 35:3456-3462.
62. Ciolkowski M, Petersen JF, Ficker M, Janaszewska A, Christensen JB, Klajnert B, Bryszewska M. 2012. Surface modification of PAMAM dendrimer improves its biocompatibility. Nanomedicine 8:815-817.
63. Saovapakhiran A, D'Emanuele A, Attwood D, Penny J. 2009. Surface modification of PAMAM dendrimers modulates the mechanism of cellular internalization. Bioconjug Chem 20:693-701.
64. Voit B, Appelhans D. 2010. Glycopolymers of various architectures-More than mimicking nature. Macromol Chem Phys 211:727-735.
65. Roy R, Zanini S, Meunier J, Romanowska A. 1993. Solid phase synthesis of dendritic sialoside inhibitors of influenza A virus haemagglutinin. J Chem Soc Chem Commun 24:1869-1872.
66. Chabre YM, Roy R. 2008. Recent trends in glycodendrimer syntheses and applications. Curr Top Med Chem 8:1237-1285.
67. Chabre YM, Roy R. 2010. Design and creativity in synthesis of multivalent neoglycoconjugates. Adv Carbohydr Chem Biochem 63:165-393.
68. Imberty A, Chabre YM, Roy R. 2008. Glycomimetics and glycodendrimers as high affinity microbial anti-adhesins. Chemistry 14:7490-7499.
69. Okada M, Aoi K. 1995. Synthesis of sugar-containing macromonomers by living ring-opening polymerization. J Macromol Sci Pure Appl Chem A32:907-914.
70. Aoi K, Itoh K, Okada M. 1995. Globular carbohydrate macromolecule sugar balls.1. Synthesis of novel sugar-persubstituted poly (amido amine) dendrimers. Macromolecules 28:5391-5393.
71. Dubber M, Lindhorst TK. 2001. Trehalose-based octopus glycosides for the synthesis of carbohydrate-centered PAMAM dendrimers and thiourea-bridged glycoclusters. Org Lett 3:4019-4022.
72. Vargas-Berenguel A, Ortega-Caballero F, Santoyo-Gonzalez F, Garcia-Lopez JJ, Gimenez-Martinez JJ, Garcia-Fuentes L, Ortiz-Salmeron E. 2002. Dendritic galactosides based on a beta-cyclodextrin core for the construction of site-specific molecular delivery systems: Synthesis and molecular recognition studies. Chemistry 8:812-827.
73. Turnbull WB, Stoddart JF. 2002. Design and synthesis of glycodendrimers. J Biotechnol 90:231-255.
74. Oliveira JM, Kotobuki N, Marques AP, Pirraco RP, Benesch J, Hirose M, Costa SA, Mano JF, Ohgushi H, Reis RL. 2008. Surface engineered carboxymethylchitosan/poly (amidoamine) dendrimer nanoparticles for intracellular targeting. Adv Funct Mater 18:1840-1853.
75. Liu KC, Yeo Y. 2013. Zwitterionic chitosan-polyamidoamine dendrimer complex nanoparticles as a pH-sensitive drug carrier. Mol Pharm 10:1695-1704.
76. Salgado AJ, Oliveira JM, Pirraco RP, Pereira VH, Fraga JS, Marques AP, Neves NM, Mano JF, Reis RL, Sousa N. 2010. Carboxymethylchitosan/poly (amidoamine) dendrimer nanoparticles in central nervous systems-regenerative medicine: Effects on neuron/glial cell viability and internalization efficiency. Macromol Biosci 10:1130-1140.
77. Princz MA, Sheardown H. 2012. Heparin-modified dendrimer crosslinked collagen matrices for the delivery of heparin-binding epidermal growth factor. J Biomed Mater Res A 100:1929-1937.
78. Woller EK, Cloninger MJ. 2001. Mannose functionalization of a sixth generation dendrimer. Biomacromolecules 2:1052-1054.
79. Ashton AR, Boyd SE, Brown CL, Nepogodiev SA, Meijer EW, Eerlings H W I, Stoddart JF. 1997. Synthesis of glycodendrimers by modification of poly (propylene imine) dendrimers. Chem Eur J 3:974-984.
80. Ramstrom O, Lohmann S, Bunyapaiboonsri T, Lehn JM. 2004. Dynamic combinatorial carbohydrate libraries: Probing the binding site of the concanavalin A lectin. Chemistry 10:1711-1715.
81. Niederhafner P, Sebestik J, Jezek J. 2008. Glycopeptide dendrimers. Part I. J Pept Sci 14:2-43.
82. Niederhafner P, Reinis M, Sebestik J, Jezek J. 2008. Glycopeptide dendrimers, part III: A review. Use of glycopeptide dendrimers in immunotherapy and diagnosis of cancer and viral diseases. J Pept Sci 14:556-587.
83. Oka H, Onaga T, Koyama T, Guo CT, Suzuki Y, Esumi Y, Hatano K, Terunuma D, Matsuoka K. 2009. Syntheses and biological evaluations of carbosilane dendrimers uniformly functionalized with sialyl alpha (2->3) lactose moieties as inhibitors for human influenza viruses. Bioorg Med Chem 17:5465-5475.
84. Sebastik J, Niederhafner P, Jezek J. 2011. Peptide and glycopeptide dendrimers and analogous dendrimeric structures and their biomedical applications. Amino Acids 40:301-370.
85. Barata TS, Shaunak S, Teo I, Zloh M, Brocchini S. 2011. Structural studies of biologically active glycosylated polyamidoamine (PAMAM) dendrimers. J Mol Model 17:2051-2060.
86. Lapolla A, Molin L, Traldi P. 2013. Protein glycation in diabetes as determined by mass spectrometry. Int J Endocrinol 2013:412103.
87. Demirci S, Emre FB, Ekiz F, Oguzkaya F, Timur S, Tanyeli C, Toppare L. 2012. Functionalization of poly-SNS-anchored carboxylic acid with Lys and PAMAM: Surface modifications for biomolecule immobilization/stabilization and bio-sensing applications. Analyst 137:4254-4261.
88. Kataoka T, Yamamoto S, Yamamoto T, Tokunaga T. 1990. Immunotherapeutic potential in guinea-pig tumor model of deoxyribonucleic acid from mycobacterium bovis BCG complexed with poly-L-lysine and carboxymethylcellulose. Jpn J Med Sci Biol 43:171-182.
89. Roberts BP, Scanlon MJ, Krippner GY, Chalmers DK. 2009. Molecular dynamics of poly (L-lysine) dendrimers with naphthalene disulfonate caps. Macromolecules 42:2775-2783.
90. Ohsaki M, Okuda T, Wada A, Hirayama T, Niidome T, Aoyagi H. 2002. In vitro gene transfection using dendritic poly (L-lysine). Bioconjugate Chem 13:510-517.
91. Kaminskas LM, Boyd BJ, Karellas P, Henderson SA, Giannis MP, Krippner GY, Porter C J H. 2007. Impact of surface derivatization of poly-L-lysine dendrimers with anionic aryisulfonate or succinate groups on intravenous pharmacokinetics and disposition. Mol Pharm 4:949-961.
92. Kaminskas LM, Boyd BJ, Karellas P, Krippner GY, Lessene R, Kelly B, Porter C J H. 2008. The impact of molecular weight and PEG chain length on the systemic pharmacokinetics of PEGylated poly L-lysine dendrimers. Mol Pharm 5:449-463.
93. Al Jamal KT, Al Jamal WT, Wang JT, Rubio N, Buddle J, Gathercole D, Zloh M, Kostarelos K. 2013. Cationic poly-L-lysine dendrimer complexes doxorubicin and delays tumor growth in vitro and in vivo. ACS Nano 7:1905-1917.
94. Fox ME, Guillaudeu S, Frechet J M J, Jerger K, Macaraeg N, Szoka FC. 2009. Synthesis and in vivo antitumor efficacy of pegylated poly (L-lysine) dendrimer-camptothecin conjugates. Mol Pharm 6:1562-1572.
95. Kaminskas LM, Wu Z, Barlow N, Krippner GY, Boyd BJ, Porter CJ. 2009. Partly-PEGylated poly-L-lysine dendrimers have reduced plasma stability and circulation times compared with fully PEGylated dendrimers. J Pharm Sci 98:3871-3875.
96. Sideratou Z, Sterioti N, Tsiourvas D, Tziveleka LA, Thanassoulas A, Nounesis G, Paleos CM. 2010. Arginine endfunctionalized poly (L-lysine) dendrigrafts for the stabilization and controlled release of insulin. J Colloid Interface Sci 351:433-441.