(306d) Synthesis and Characterization of Hyperbranched and Dendritic Poly(N-isopropylacryalmide) with Physiological Transition Temperatures for Targeted Drug Delivery | AIChE

(306d) Synthesis and Characterization of Hyperbranched and Dendritic Poly(N-isopropylacryalmide) with Physiological Transition Temperatures for Targeted Drug Delivery


Chang, K. - Presenter, Georgia Institute of Technology
Bergman, L. A. - Presenter, Georgia Institute of Technology
Taite, L. J. - Presenter, Georgia Institute of Technoloy

Background: Targeted drug delivery has long been a goal of the medical and drug development community. Highly branched molecules with large numbers of functionalizable end groups are currently being used for this purpose. We aim to synthesize hyperbranched or dendritic poly(n-isopropyl acrylamide) (pNIPAAm), a thermally responsive polymer,  and modify it for high thermal transition properties in order to make a hybrid drug delivery vehicle that provides targeted and controlled release of drugs based on external stimuli.

By creating dendritic pNIPAAm, we aim to combine the drug loading and targeted delivery aspects of dendritic macromolecules with the thermally responsive properties of pNIPAAm.  We will eventually couple this technology with nanoshell technology which has been shown to heat up significantly under the presence of certain wavelengths of light.  This combination will form a multifunctional hybrid system for targeted drug delivery.

Hyperbranched polymers have many similar properties with dendrimers including globular structure with numerous end groups and space to load drugs. Hyperbranched systems are usually not as well defined as dendritic systems; however, they are far less labor intensive to synthesize.  Hyperbranched pNIPAAm synthesis has been reported previously[1-2]; however, to our knowledge, the manipulation of the LCST to higher temperatures has yet to be presented. 

Reversible Addition-Fragmentation Chain Transfer (RAFT) polymerization, a well established method for controlled ?living? radical polymerization, was used to create hyperbranched polymers[4].  It also allowed for the efficient inclusion of copolymers.  In this study, a copolymer with acrylic acid (AAc) was made in order to raise the LCST of pNIPAAm from its normal 32°C to > 45°C so that the transition will be induced above body temperature for in vivo applications.  A truly dendritic pNIPAAm was also created.

Methods: Three different CTAs were synthesized and used to form linear and hyperbranched pNIPAAm. S,S'bis(α,α'-dimethyl-α''-acetic acid)trithiocarbonate (CTA1), 4-Vinylbenzyl-imidazole Dithioate (CTA2), and 1-[3-(2-Methyl-2-dodecylsulfanylthiocarboxylsulfanyl-propionyloxy) propyl]-1H-[1,2,3]triazol-4-ylmethyl Acrylate (CTA3) were synthesized as published[1-3].  Polymerization was carried out with the CTAs under typical conditions[2-3]. 

Solid phase dendritic polymer synthesis was achieved by conjugating CTA1 to 2-chloryltritylchloride resin, polymerizing, biotinylating the polymer[5], and reacting with streptavidin.  The resulting branch was then reacted with a previously biotinylated polymer branch to create further dendrimer generations.

Results: Characterization of polymer was conducted using NMR spectrometry and gel permeation chromatography.  LCST was determined using UV-Visible Spectrometry.


Figure 1 shows confirmation of pNIPAAm synthesis and sharp thermal transition temperatures.  Due to the loss of degrees of freedom in hyperbranching, polymers polymerized with CTA2 and CTA3 have a lower LCST than linear pNIPAAm.  This was increased in the copolymers with AAc as seen in Figure 2.


With 10% AAc, the linear pNIPAAm had a very high thermal transition temperature of ~78°C; however, with the natural decrease of LCST due to hyperbranching, CTA2 polymerized pNIPAAm-co-AAc showed a sharp LCST at 45°C and CTA3 showed an LCST of 60°C.  Polydispersities ranging from 1.01 to 1.13 were observed.

The 2-Chloryltritylchloride resin conjugation of CTA1 gave yields of up to 88%.  Branching reactions with streptavidin and biotinylated pNIPAAm have been confirmed.  Polymerization on the resin is still under investigation.

Conclusions:  The results show that we were able to create well defined linear and hyperbranched pNIPAAm chains with high thermal transition temperatures.  Solid phase dendrimer synthesis also shows promise with the success of conjugation and branching.  Future experiments will be done to test the effects of drug loading and to functionalize the surface with different targeting peptides.


1.       Lai JT. et al. Macromolecules 2002;35:6754-6756

2.       Vogt AP. et al. Macromolecules. 2008;41:7368-7373

3.       Carter S. et al. Macromolecular Bioscience. 2005;5:373-378

4.       Chiefari J. et al. Macromolecules 1998;31:5559-5562

5.       Narain R. et al. Langmuir 2007; 23:6299-6304