Amino acid-functionalized dendrimers with heterobifunctional chemoselective peripheral groups for drug delivery applications.
Dendrimers have emerged as multifunctional carriers for targeted drug delivery, gene delivery and imaging. Improving the functional versatility at the surface for carrying multiple conjugation reactions is becoming vital. Typically, generation four polyamidoamine (G4-PAMAM) dendrimers bear approximately 64 symmetrical end groups, often requiring different spacers to conjugate various functional groups (drugs and targeting moities), increasing the synthetic steps. In the present study, a simple one-step synthesis to convert each symmetrical end group of G4-PAMAM dendrimers into two reactive, distinct orthogonal and chemoselective groups is described. A near-complete end-capping of the dendrimers (87-93%) with amino acids results in heterobifunctional G4-PAMAM dendrimers bearing a very high (> or = 110) diverse peripheral end groups (OH+NHBoc, OH+COOMe, SH+NHBoc, and COOH+NHBoc). Postfunctionalization ability of these dendrimers was evaluated. The heterobifunctional groups at the dendrimer periphery could be chemoselectively conjugated to multiple moities such as drugs (indomethacin and dexamethasone) and drugs and imaging agents (dexamethasone and FITC). These conjugations could be achieved in immediate succession without functional group conversions, eliminating the additional elaborate synthetic steps traditionally required to append specific linkers. Furthermore, one of the two functional handles at periphery was used to develop in situ forming hydrogels, whereas the other handle could be used for conjugating the drugs (e.g., dexamethasone). The heterobifunctional dendrimers with either "NH(2) or SH (thiopyridyl protected form)" terminations showed in situ hydrogel formation by cross-linking with N-hydroxysuccinimide or thiol-terminated multiarm polyethylene glycol (20 kDa). The choice of amino acids as versatile linkers would enable biocompatible dendrimer scaffolds for use in drug delivery. Zeta-potential measurements showed drastic lowering of the charge on G4-PAMAM-NH(2) dendrimers by end-capping with amino acids, whereas in the case of neutral G4-PAMAM-OH dendrimers, the charge did not increase or decrease substantially. The in vitro cytotoxicity and hemolysis assay showed that the heterobifunctional dendrimers were noncytotoxic in the 100 ng/mL to 1 mg/mL concentration range. With this study, we demonstrate the development of biocompatible dendrimers bearing multiple orthogonal surface groups, enabling the attachment of drugs, imaging agents, and gel formation using minimal synthetic steps.
Navath
Raghavendra S
RS
Department of Chemical Engineering and Material Science, Wayne State University, Detroit, Michigan 48202, USA.
Menjoge
Anupa R
AR
Wang
Bing
B
Romero
Roberto
R
Kannan
Sujatha
S
Kannan
Rangaramanujam M
RM
D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D000818:Animals; D001672:Biocompatible Materials / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D050091:Dendrimers / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D003907:Dexamethasone / Q000008:administration & dosage / Q000737:chemistry; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D016503:Drug Delivery Systems; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D020100:Hydrogels; D007213:Indomethacin / Q000008:administration & dosage / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010316:Particle Size; D011817:Rabbits; D012542:Scattering, Radiation; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D000596:Amino Acids; D001672:Biocompatible Materials; D050091:Dendrimers; D004337:Drug Carriers; D020100:Hydrogels; C104700:PAMAM Starburst; D003907:Dexamethasone; D007213:Indomethacin