Xia-Bin Jing*,  Xue-Si Chen

State Key Lab of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry (CIAC), Chinese Academy of Sciences, Changchun, Jilin, 130022, China

The investigations of biomedical polymers in CIAC in recent years are summarized:

A. Modification of aliphatic polyesters

Aliphatic polyesters have many excellent advantages. But their disadvantages are obvious. They are hydrophobic. They do not have active functional groups. And they are electrically neutral. These shortcomings limit their application, especially in medical fields. Therefore, we tried to chemically modify polylactides by copolymerizing with proper monomers, such as ethylene oxide, amino acids and others. In this direction, we have prepared diblock and triblock copolymers of lactide or ε-caprolactone with ethylene oxide, four-armed copolymer PCL-PEO, diblock copolymers of lactide with glutamate or triblock copolymers of the both with polyethylene glycol (PEG), and diblock copolymer of sterospecific PLA with PEG. Some monomers with functional groups were synthesized, such as 2, 2- bis(methylol)propionate, 2-methyl-2-(2- carboxyethyl)-1,3-propylene carbonate. By incorporating such monomers into PLA, side-chain carboxy and other groups can be introduced. They are further linked to related moieties to render required biological activity.

B. Electrospun ultrafine fibers for drug carriers

PLA, PCL and PLGA are electrospun into ultrafine fibers and typical drugs are successfully capsulated in the fibers. The medicated fiber mats release the drugs in the kinetics of nearly zero order in the presence of proper enzymes, such as lipase PL for PCL and proteinase K for PLA or PLGA. These results show that such medicated fiber mats would be promising formulation for postoperative local chemotherapy.

C. Poly(ε-caprolactone) polyurethane shape memory materials

PCL with two terminal OH groups are prepared and are reacted with diisocyanates and ethylene glycol to obtain PCL polyurethanes (PCLU) with various PCL lengths and hard-to-soft segment ratios. Their shape memory behaviors are examined as a function of PCL length and hard-to-soft ratio. It is demonstrated that the characteristic temperatures for shape memory of PCLU are near room temperature and near body temperature. That means that it may find important medical applications, such as esophagus stent.

D. Diblock copolymer conjugate of antitumor drugs

Paclitaxel is a well known antitumor drug. Because it is highly hydrophobic, a mixture of polyepoxy(caster oil), Chremophor EL) and ethanol is used as its medium. Many patients exhibit hypersensitivity to this formulation. To develop a new formulation for paclitaxel, we synthesized a diblock copolymer PEG-PLA, converted its hydroxyl end-group into carboxyl group, and finally reacted it with paclitaxel to achieve a covalent linkage between the polymer and the drug. Because PEG-PLA is amphiphilic and paclitaxel is hydrophobic, PEG-PLA- paclitaxel can spontaneously form micelles in an aqueous system with paclitaxel in the core region and PEG blocks in the shell region. In this way, a stable suspension may be obtained. Because paclitaxel is combined to PLA through an ester linkage, it may be released via hydrolysis of the ester group and the biodegradation of PLA blocks would speed up its release. In fact, PEG-PLA-paclitaxel showed quite high antitumor activity against human liver cancer H7402 cells.

E. Animal experiments on the feasibilities of PLGA CBD stents

After copolymerization of lactide with other monomers, the mechanical property and degradation rate of the products can be adjusted to fulfill the requirement of definite medical applications. Take common bile duct (CBD) stent as an example. A random copolymer PLGA was chosen as the stent material. It lasted 24 days in in-vitro experiment. Small tubes of ~1mm diameter were implanted into the CBD’s of 60 rats and 8 dogs. By monitoring the change in the tubes and in the liver function of the animals, it was shown that the tubes degraded gradually and disappeared in 4-5 weeks from CBD, and the liver function entirely recovered in 8 weeks.

References

1. Longhai Piao, Zhongli Dai, Mingxiao Deng, Xuesi Chen, Xiabin Jing*. Synthesis and characterization of PCL/PEG/PCL triblock copolymers by using calcium catalyst. Polymer, 2003, 44(7): 2025-2031.

2. Longhai Piao, Mingxiao Deng, Xuesi Chen, Liansheng Jiang, Xiabin Jing*. Ring-opening polymerization of ε-caprolactone and L-lactide using organic amino calcium catalyst.  Polymer, 2003, 44(8): 2331-2336.

3. Jing Zeng, Xiaoyi Xu, Xuesi Chen, Qizhi Liang, Xinchao Bian, Lixin Yang and Xiabin Jing*. Biodegradable electrospun fibers for drug delivery.  J. of Controlled Release, 2003, 92, 227-231.

4. Rong Guangzhuo, Deng Mingxiao, Deng Chao, Tang Zhaohui, Piao Longhai, Chen Xuesi*, Jing Xiabin. Synthesis of poly(e-caprolactone)-b-poly(γ-benzyl-l-glutamic acid) block copolymer using amino organic calcium., Biomacromolecules 2003, 4(6): 1800-1804.

5. Zhaohui Tang, Xuesi Chen*, Qizhi Liang, Xinchao Bian, Lixin Yang, Longhai Piao, and Xiabin Jing. Strontium-based initiator system for ring-opening polymerization of cyclic esters. Journal of Polymer Science Part A: Polymer Chemistry, 2003, 41(13),1934-1941.

6. Mingxiao Deng, Rong Wang, Guangzhuo Rong, Jingru Sun, Xuefei Zhang, Xuesi Chen*, Xiabin Jing. Synthesis of a novel structural triblock copolymer of poly(γ-benzyl-l-glutamic acid)-b-poly(ethylene oxide)-b-poly(e-caprolactone). Biomaterials, 2004, 25, 3553-3558.