Janus PEG-Based Dendrimers for Use in Combination Therapy: Controlled Multi-Drug Loading and Sequential Release
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- 作者：Aaron L. Acton ; Cristina Fante ; Brian Flatley ; Stefano Burattini ; Ian W. Hamley ; Zuowei Wang ; Francesca Greco ; Wayne Hayes
- 刊名：Biomacromolecules
- 出版年：2013
- 出版时间：February 11, 2013
- 年：2013
- 卷：14
- 期：2
- 页码：564-574
- 全文大小：754K
- 年卷期：v.14,no.2(February 11, 2013)
- ISSN：1526-4602
文摘
The increasing use of drug combinations to treat disease states, such as cancer, calls for improved delivery systems that are able to deliver multiple agents. Herein, we report a series of novel Janus dendrimers with potential for use in combination therapy. Different generations (first and second) of PEG-based dendrons containing two different 鈥渕odel drugs鈥? benzyl alcohol (BA) and 3-phenylpropionic acid (PPA), were synthesized. BA and PPA were attached via two different linkers (carbonate and ester, respectively) to promote differential drug release. The four dendrons were coupled together via (3 + 2) cycloaddition chemistries to afford four Janus dendrimers, which contained varying amounts and different ratios of BA and PPA, namely, (BA)2-G1-G1-(PPA)2, (BA)4-G2-G1-(PPA)2, (BA)2-G1-G2-(PPA)4, and (BA)4-G2-G2-(PPA)4. Release studies in plasma showed that the dendrimers provided sequential release of the two model drugs, with BA being released faster than PPA from all of the dendrons. The different dendrimers allowed delivery of increasing amounts (0.15鈥?.30 mM) and in exact molecular ratios (1:2; 2:1; 1:2; 2:2) of the two model drug compounds. The dendrimers were noncytotoxic (100% viability at 1 mg/mL) toward human umbilical vein endothelial cells (HUVEC) and nontoxic toward red blood cells, as confirmed by hemolysis studies. These studies demonstrate that these Janus PEG-based dendrimers offer great potential for the delivery of drugs via combination therapy.