Editorial pubs.acs.org/molecularpharmaceutics
Beyond the Great Wall: Recent Advances in Molecular Pharmaceutics Research in China
W
nificant prostate carcinoma targeting ability. As peptides have been wildly used as targeting ligands, their stability in the circulation remains a concern. Therefore, in Prof. Weiyue Lu’s article, a D-isomer of Angiopep-2 (a peptide with the ability to trigger transcytosis and traverse the BBB) was designed by retro-inverso isomerization to avoid degradation by enzymes in the bloodstream. To promote the clinical translation of targeted drug delivery systems, clinically approved materials and endogenous molecules are most favorable in these studies. A tumor environment responsive doxorubicin-loaded nanoparticle was developed by Prof. Junfeng Zhang and Lei Dong for targeted cancer therapy based on clinically approved materials, including cationic gelatin and human serum albumin. One of the important issues in targeted drug delivery is to improve the stability of delivery vehicles in circulation to ensure that the drug molecules can reach their desired targets. This has been addressed in Prof. Zhonggui He’s article by designing a nonspherical poly(ethylene glycol) (PEG)-stabilized bilayer nanodisk, which showed the extended blood circulation and improved tumor distribution for doxorubicin. Similarly, to enhance the stability of the carrier in the bloodstream, in Prof. Chi Wu’s study, carborane−PEG conjugates were synthesized. The resulting self-assembly vesicles are potentially multifunctional in biomedical applications, serving as a boron neutron capture therapy (BNCT) agent, a hydrophilic drug carrier, and a diagnostic imaging fluorescent probe. Another exciting area in molecular pharmaceutics research is gene delivery, which has achieved significant progress in the treatment of some major diseases. However, many challenges and obstacles in terms of in vivo delivery remain to be solved. There are several biological barriers to be overcome by the gene carriers. To satisfy both the criteria of gene packaging and gene release in the cytoplasm in time, Prof. Tuo Jin and Xiaoling Zhang designed and developed a novel cationic polymer, polyspermine, by condensing two endogenous molecules, spermine and glyoxal. The poly linkage structure was sufficiently stable under neutral conditions but dissociative at endosomal pH. To overcome high cytotoxicity and nontargeted gene delivery of PEI-25K, in Prof. Jianping Zhou and Yu Wang’s work, an antitumor drug, eprosartan (ES), was first conjugated with PEI-1.8K via the pH-sensitive bis-amide bond. The resulting ES−PEI conjugate (ESP) could mediate efficient intracellular transfection, and the ESP/p53 codelivery system possessed very high tumor-targeting capacity, strong antitumor efficacy, and synergistic antiangiogenesis effect. In Prof. Jianqing Gao’s work, a spermine-mannan based delivery system was proven to be hepatic-targeting and was capable of prolonging the gene retention period in the liver. To achieve targeted gene delivery to brain tumor, in Prof. Chen Jiang’s
hen speaking of China, one may immediately think of the ancient Great Wall, the lovely Giant Panda, and the irresistible Chinese Cuisine. Over the past 30 years, however, China has also experienced breathtaking economic growth and remarkable transformation of its society. As China strives to focus on innovation and transitioning from the world’s low-cost manufacturing hub to a high-tech driven economy, the country’s total expenditure on research and development has increased by 23% per annum on average during the last 10 years. With a rapidly aging society, the Chinese government has emphasized the improvement of healthcare and biomedical research, with approximately 17% of total government research funding allocated to medical research. The National Natural Science Foundation (NSFC) of China has recently announced several research initiatives for basic biomedical research and translational medicines. These visionary new government policies have significantly stimulated the scientific research, boosting its total research publication ranking to the second highest nation in the world. This was also accompanied by an impressive annual increase of new patent applications filed and new patents issued. As another major initiative to boost its technology competitiveness, the government also encourages its young scientists to go abroad in order to be trained by some of the world’s most intelligent minds. Upon their return, major investments were also made to ensure their success. Many of our colleagues in the pharmaceutical sciences field and ourselves have benefited from this initiative. In this theme issue of “Recent Molecular Pharmaceutical Development in China”, we would like to highlight some of the most exciting research done by our colleagues from some of the most prestigious pharmaceutical research institutions in China. Targeted drug delivery has been one of the most popular topics in molecular pharmaceutics. Several unique targeting strategies have been explored in this theme issue. Selective targeting to cancer cells requires the discovery of specific markers, which can efficiently bind and facilitate the uptake of nanocarriers and macromolecules. In Prof. Qiang Zhang’s manuscript, chlorotoxin (ClTx), a peptide, which can specifically bind to matrix metalloproteinase 2 (MMP2), was employed to modify liposome. In vitro and in vivo data showed that the ClTx-modified liposomes increased drug delivery to metastatic breast cancers. Targeting ligands displayed on a liposome surface have been shown to mediate specific interactions and drug delivery to target cells. However, they also affect liposome distribution in vivo, as well as the tissue extravasation processes after iv injection. In Prof. Yuhong Xu’s study, an EGFR targeting peptide GE11 was incorporated on liposome surfaces in addition to PEG at different densities, and they found that the densities of surface ligand and PEG were critical to target cell binding in vitro as well as pharmacokinetic profiles in vivo. In Prof. Yuan Huang’s work, galectin-3-binding peptide, G3-C12 was attached to N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers, which exhibited sig© 2014 American Chemical Society
Special Issue: Recent Molecular Pharmaceutical Development in China Published: October 6, 2014 3231
dx.doi.org/10.1021/mp5005542 | Mol. Pharmaceutics 2014, 11, 3231−3232
Molecular Pharmaceutics
Editorial
study, a bacteria derived peptide was used to modify a dendrigraft poly‑L‑lysine (DGL) self-assembling nanoplatform. Multidrug resistance is another major barrier for cancer treatment. In Prof. Yaping Li’s article, to overcome the multidrug resistance (MDR) in human hepatocellular carcinoma, the codelivery of sorafenib and survivin shRNA was successfully achieved with TPGS nanoparticles, resulting in synergistic effects in reversing MDR, suppressing tumor growth and angiogenesis. Meanwhile, Prof. Yongzhuo Huang and coauthors developed a strategy of codelivery of apoptotic AVPI peptide and p53 DNA as apoptosis-induction adjuvant therapy for combating the resistant breast cancer. As biopharmaceuticals have made a profound impact on the development of the pharmaceutical industry, the lack of efficient oral delivery systems remains one of the challenging issues. In this issue, Prof. Wei Liang developed an effective strategy to improve the intestinal stability of oral protein drugs as demonstrated by using PEG 400, which can alter the enzymatic activity of α-chymotrypsin and thus protected insulin from enzymatic degradation. To achieve a longer sustainedrelease pattern of nanocarriers, in Prof. Xun Sun’s work, the complexes consisting of thymopentin peptide and phospholipids were developed and incorporated into hydrophobic nanoparticles, which showed the release duration longer than 7 days after a single subcutaneous injection in Wistar rats. Last but not least, some other interesting studies are also presented. In Prof. Gong’s work, a novel injectable in situ forming gel system was prepared using small molecule materials, including phospholipids, medium chain triglycerides, and ethanol. This in situ forming gel system has a well-defined molecule structure, a high degree of safety, and better biocompatible characteristics. Prof. Xing-Jie Liang and Kaiyong Cai developed a novel multifunctional metal nanorattle structure for simultaneous MR imaging, photothermal ablation, and potential delivery of different chemotherapy. As summarized above, we hope the work presented in these manuscripts can help you to appreciate the most recent advances in molecular pharmaceutics in China. We are confident that the vast Chinese pharmaceutical market, the unique medical needs of the Chinese demographic, and the clinically proven Chinese herbal medicine will offer many opportunities for international collaboration. We also hope this theme issue will provide an excellent opportunity to facilitate the communication and collaboration of our Chinese colleagues with the international pharmaceutical science community. Lastly, we want to thank all contributing authors who have kindly agreed to contribute upon our invitation. Your hard work has made this theme issue a success. Thank you!
Yuan Huang,* Guest Editor Xun Sun,* Guest Editor
■
West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, China, 610041
AUTHOR INFORMATION
Corresponding Authors
*(Y.H.) E-mail: [email protected] *(X.S.) E-mail: [email protected] Notes
Views expressed in this editorial are those of the authors and not necessarily the views of the ACS.
3232
dx.doi.org/10.1021/mp5005542 | Mol. Pharmaceutics 2014, 11, 3231−3232
Beyond the Great Wall: Recent Advances in Molecular Pharmaceutics Research in China
W
nificant prostate carcinoma targeting ability. As peptides have been wildly used as targeting ligands, their stability in the circulation remains a concern. Therefore, in Prof. Weiyue Lu’s article, a D-isomer of Angiopep-2 (a peptide with the ability to trigger transcytosis and traverse the BBB) was designed by retro-inverso isomerization to avoid degradation by enzymes in the bloodstream. To promote the clinical translation of targeted drug delivery systems, clinically approved materials and endogenous molecules are most favorable in these studies. A tumor environment responsive doxorubicin-loaded nanoparticle was developed by Prof. Junfeng Zhang and Lei Dong for targeted cancer therapy based on clinically approved materials, including cationic gelatin and human serum albumin. One of the important issues in targeted drug delivery is to improve the stability of delivery vehicles in circulation to ensure that the drug molecules can reach their desired targets. This has been addressed in Prof. Zhonggui He’s article by designing a nonspherical poly(ethylene glycol) (PEG)-stabilized bilayer nanodisk, which showed the extended blood circulation and improved tumor distribution for doxorubicin. Similarly, to enhance the stability of the carrier in the bloodstream, in Prof. Chi Wu’s study, carborane−PEG conjugates were synthesized. The resulting self-assembly vesicles are potentially multifunctional in biomedical applications, serving as a boron neutron capture therapy (BNCT) agent, a hydrophilic drug carrier, and a diagnostic imaging fluorescent probe. Another exciting area in molecular pharmaceutics research is gene delivery, which has achieved significant progress in the treatment of some major diseases. However, many challenges and obstacles in terms of in vivo delivery remain to be solved. There are several biological barriers to be overcome by the gene carriers. To satisfy both the criteria of gene packaging and gene release in the cytoplasm in time, Prof. Tuo Jin and Xiaoling Zhang designed and developed a novel cationic polymer, polyspermine, by condensing two endogenous molecules, spermine and glyoxal. The poly linkage structure was sufficiently stable under neutral conditions but dissociative at endosomal pH. To overcome high cytotoxicity and nontargeted gene delivery of PEI-25K, in Prof. Jianping Zhou and Yu Wang’s work, an antitumor drug, eprosartan (ES), was first conjugated with PEI-1.8K via the pH-sensitive bis-amide bond. The resulting ES−PEI conjugate (ESP) could mediate efficient intracellular transfection, and the ESP/p53 codelivery system possessed very high tumor-targeting capacity, strong antitumor efficacy, and synergistic antiangiogenesis effect. In Prof. Jianqing Gao’s work, a spermine-mannan based delivery system was proven to be hepatic-targeting and was capable of prolonging the gene retention period in the liver. To achieve targeted gene delivery to brain tumor, in Prof. Chen Jiang’s
hen speaking of China, one may immediately think of the ancient Great Wall, the lovely Giant Panda, and the irresistible Chinese Cuisine. Over the past 30 years, however, China has also experienced breathtaking economic growth and remarkable transformation of its society. As China strives to focus on innovation and transitioning from the world’s low-cost manufacturing hub to a high-tech driven economy, the country’s total expenditure on research and development has increased by 23% per annum on average during the last 10 years. With a rapidly aging society, the Chinese government has emphasized the improvement of healthcare and biomedical research, with approximately 17% of total government research funding allocated to medical research. The National Natural Science Foundation (NSFC) of China has recently announced several research initiatives for basic biomedical research and translational medicines. These visionary new government policies have significantly stimulated the scientific research, boosting its total research publication ranking to the second highest nation in the world. This was also accompanied by an impressive annual increase of new patent applications filed and new patents issued. As another major initiative to boost its technology competitiveness, the government also encourages its young scientists to go abroad in order to be trained by some of the world’s most intelligent minds. Upon their return, major investments were also made to ensure their success. Many of our colleagues in the pharmaceutical sciences field and ourselves have benefited from this initiative. In this theme issue of “Recent Molecular Pharmaceutical Development in China”, we would like to highlight some of the most exciting research done by our colleagues from some of the most prestigious pharmaceutical research institutions in China. Targeted drug delivery has been one of the most popular topics in molecular pharmaceutics. Several unique targeting strategies have been explored in this theme issue. Selective targeting to cancer cells requires the discovery of specific markers, which can efficiently bind and facilitate the uptake of nanocarriers and macromolecules. In Prof. Qiang Zhang’s manuscript, chlorotoxin (ClTx), a peptide, which can specifically bind to matrix metalloproteinase 2 (MMP2), was employed to modify liposome. In vitro and in vivo data showed that the ClTx-modified liposomes increased drug delivery to metastatic breast cancers. Targeting ligands displayed on a liposome surface have been shown to mediate specific interactions and drug delivery to target cells. However, they also affect liposome distribution in vivo, as well as the tissue extravasation processes after iv injection. In Prof. Yuhong Xu’s study, an EGFR targeting peptide GE11 was incorporated on liposome surfaces in addition to PEG at different densities, and they found that the densities of surface ligand and PEG were critical to target cell binding in vitro as well as pharmacokinetic profiles in vivo. In Prof. Yuan Huang’s work, galectin-3-binding peptide, G3-C12 was attached to N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers, which exhibited sig© 2014 American Chemical Society
Special Issue: Recent Molecular Pharmaceutical Development in China Published: October 6, 2014 3231
dx.doi.org/10.1021/mp5005542 | Mol. Pharmaceutics 2014, 11, 3231−3232
Molecular Pharmaceutics
Editorial
study, a bacteria derived peptide was used to modify a dendrigraft poly‑L‑lysine (DGL) self-assembling nanoplatform. Multidrug resistance is another major barrier for cancer treatment. In Prof. Yaping Li’s article, to overcome the multidrug resistance (MDR) in human hepatocellular carcinoma, the codelivery of sorafenib and survivin shRNA was successfully achieved with TPGS nanoparticles, resulting in synergistic effects in reversing MDR, suppressing tumor growth and angiogenesis. Meanwhile, Prof. Yongzhuo Huang and coauthors developed a strategy of codelivery of apoptotic AVPI peptide and p53 DNA as apoptosis-induction adjuvant therapy for combating the resistant breast cancer. As biopharmaceuticals have made a profound impact on the development of the pharmaceutical industry, the lack of efficient oral delivery systems remains one of the challenging issues. In this issue, Prof. Wei Liang developed an effective strategy to improve the intestinal stability of oral protein drugs as demonstrated by using PEG 400, which can alter the enzymatic activity of α-chymotrypsin and thus protected insulin from enzymatic degradation. To achieve a longer sustainedrelease pattern of nanocarriers, in Prof. Xun Sun’s work, the complexes consisting of thymopentin peptide and phospholipids were developed and incorporated into hydrophobic nanoparticles, which showed the release duration longer than 7 days after a single subcutaneous injection in Wistar rats. Last but not least, some other interesting studies are also presented. In Prof. Gong’s work, a novel injectable in situ forming gel system was prepared using small molecule materials, including phospholipids, medium chain triglycerides, and ethanol. This in situ forming gel system has a well-defined molecule structure, a high degree of safety, and better biocompatible characteristics. Prof. Xing-Jie Liang and Kaiyong Cai developed a novel multifunctional metal nanorattle structure for simultaneous MR imaging, photothermal ablation, and potential delivery of different chemotherapy. As summarized above, we hope the work presented in these manuscripts can help you to appreciate the most recent advances in molecular pharmaceutics in China. We are confident that the vast Chinese pharmaceutical market, the unique medical needs of the Chinese demographic, and the clinically proven Chinese herbal medicine will offer many opportunities for international collaboration. We also hope this theme issue will provide an excellent opportunity to facilitate the communication and collaboration of our Chinese colleagues with the international pharmaceutical science community. Lastly, we want to thank all contributing authors who have kindly agreed to contribute upon our invitation. Your hard work has made this theme issue a success. Thank you!
Yuan Huang,* Guest Editor Xun Sun,* Guest Editor
■
West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, China, 610041
AUTHOR INFORMATION
Corresponding Authors
*(Y.H.) E-mail: [email protected] *(X.S.) E-mail: [email protected] Notes
Views expressed in this editorial are those of the authors and not necessarily the views of the ACS.
3232
dx.doi.org/10.1021/mp5005542 | Mol. Pharmaceutics 2014, 11, 3231−3232
