1. Hu Yang, Stephanie T. Lopina
Synthesis and Characterization of Drug Contained Poly (ethylene oxide) Star Polymer
Hu Yang, Stephanie T. Lopina
Department of Chemical Engineering, The University of Akron, Akron, OH 44325, USA ,
ABSTRACT SUMMERY:
A novel synthesis method to realize the easy attachment of mono-functionalized linear polymer to dendrimer core is described here.
Keyword: PAMAM dendrimer, Drug delivery, Poly (ethylene oxide), Star polymer
INTRODUCTION:
A drug delivery scaffold was designed and built up based on the PEG star polymer. Poly (ethylene glycol) (PEG) star polymer was constructed by using EDA core Starburst polyamidoamine (PAMAM) dendrimer and diamine PEG. One of the amine groups in diamine PEG was blocked by (Boc)2 O first. Penicillin was attached to short ( MW) PEG chains via amide linkages by reacting with the free amine group. Then those arms were attached to the dendrimer core via carbonate linkages after the blocked chain ends were deprotected into free amine groups by removing the BOC group.  
Drug Delivery Scaffold Constructinon Route
FTIR spectra of intermediates
EXPERIMENTAL METHODS:
Preparation of PEG-Penicillin Conjugate
The relatively pure mono-protected diamine PEG (ii) could be obtained by simple batch-wise ion exchange chromatographic separation of charged and uncharged species [1]. Penicillin-N-hydroxysuccinimidyl ester (iv) was achieved, using NHS and DCC. The conjugation of amine-containing PEG with carboxyl-containing drug could be carried out following protocols described in previous literature [2]. The product (v) was treated with TFA for about 20 minutes to remove the Boc group for further reaction.
Preparation of Penicillin Contained Poly (ethylene oxide) Star Polymer
The dried dendrimer core was dissolved in cyclohexane. Derivatized PEG was added to the dendrimer solution combined with NHS and DCC maintaining a mole ratio of drug-PEG-NH2 to dendrimer carboxyl of about The solution was stirred for 2 hours after which it is assumed that the reaction has gone to completion. Unconjugated, mono-protected PEG was added in excess to fill all remaining dendritic sites. The reaction between the dendrimer core and linear PEO will result in the formation of stars with short arms attached to drug shielded by long arms. This star polymer was separated from unreacted linear heterofunctional PEG via a centrifuge method. The presence of unreacted PEO remaining in solution was monitored by injecting a sample of both permeate (solution passing through the membrane) and retentate (solution retained by the membrane) into the GPC/LS[3].
RESULTS AND DISCUSSION:
A new route for the synthesis of drug contained star polymers, starting form symmetric homo-bifunctional groups and a dendrimer core, was shown in the reaction scheme. The reaction occurs through a functionalized end group at one end of the PEG molecule whereas the protected end group prevents the creation of loops by reactions at both ends [1]. The mono-protected homo-bifunctional PEG was later reacted with a dendrimer core to synthesize the star shaped polymer. The mono-protected group can be reduced by treatment with TFA to NH2.
We used batch-wise ion exchange chromatography ( CM-25 sephadex packing) to collect PEG with amine termini and PEG with BOC termini since the batch process has advantages over column methods. Batch processes are rapid, and the problems of packing, channeling, and dry columns are avoided.
Batch-wise ion exchange chromatography involves mixing and stirring equilibrated exchanger directly with the solute mixture to be separated. After an equilibration time, the slurry is filtered and washed with buffer. The ion exchanger can be chosen so that the desired solute is adsorbed onto the exchanger or remains unbound in solution. The desired solute is bound to the exchanger. It is removed by suspending the exchanger in a buffer of greater ionic strength or different pH.
FTIR spectrum were used to confirm the structures of intermediates.
CONCLUSIONS:
The technique described here makes it possible to build up a drug delivery system based on PEG-PAMAM star polymer. We will further our research by combining ligand to dendrimer together with drug to construct a targeted drug delivery system.
ACKNOWLEDGMENTS:
The authors gratefully acknowledge funding from an NSF CAREER award, BES , a University of Akron Faculty Research Grant, FRG-1484, and a Sigma Xi Grant in Aid of Research.
REFERENCES:
[1] Ehteshami GR, Sharma SD, Porath J, Guzman RZ. React Funct Polym 1997; 35:135.
[2] Herman S, Hooftman G, Schacht E. J Bioact Comp Polym 1995; 10:145.
[3] Merrill EW, Yen DR, Sagar A. US Patent 5,830,986, 1998