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Li W.,International Medical University | Li W.,National Engineering Research Center for Antibody Medicine | Feng S.,National University of Singapore | Guo Y.,International Medical University | And 2 more authors.
Nanomedicine | Year: 2012

Block copolymer micelles have shown great potential in drug delivery systems, not only for overcoming the drawbacks of small agents such as water insolubility and wide distribution in normal tissues, but also for avoiding traditional nanoparticle formulation shortcomings, including in vivo instability and fast clearance from the blood. However, for translating micellar formulations to clinical practice, it is essential to overcome the many in vivo obstacles. Surmounting these barriers strongly depends on micellar physicochemical properties, which can be further optimized by the unique physiological aspects of solid tumors such as low pH, high temperature and the presence of abnormal vessels. Herein, based on the Flory parameter and scaling theory, the fundamental mechanisms and correlations in vitro/in vivo between self assembly, drug loading and release, stability, intracellular delivery and in vivo distribution, as well as micellar composition, size and microstructural tailoring are systematically revisited. The methods for enhancing micellar performance in solid tumors were consequently proposed through well-defined core-corona structure tailoring. © 2012 Future Medicine Ltd.

Wang S.,Shanghai JiaoTong University | Chen C.,Shanghai JiaoTong University | Meng Y.,International Medical University | Hu S.,International Medical University | And 11 more authors.
Cancer Letters | Year: 2012

Despite the effectiveness of the anti-ErbB2 humanized antibody trastuzumab, less than 35% of patients with ErbB2-overexpressing breast cancer respond to the treatment. Here we engineered an anti-EGFR/ErbB2 bispecific antibody (TC-BsAb) using trastuzumab and cetuximab, an anti-EGFR chimeric antibody. TC-BsAb treatment led to internalization of both EGFR and ErbB2, whereas trastuzumab and cetuximab, either alone or in combination, failed to induce ErbB2 internalization. Both in vitro and in vivo experiments indicated that TC-BsAb was significantly more potent in inhibiting the growth of breast cancer cell lines than trastuzumab, cetuximab, and trastuzumab plus cetuximab, suggesting its potential use for treating breast cancer. © 2012 Elsevier Ireland Ltd.

Li B.,International Medical University | Li B.,National Engineering Research Center for Antibody Medicine | Zhao L.,International Medical University | Wang C.,Shanghai JiaoTong University | And 10 more authors.
Journal of Biological Chemistry | Year: 2010

Understanding the evolutionary mechanism that acts at the interfaces of protein-protein complexes is a fundamental issue with high interest for delineating the macromolecular complexes and networks responsible for regulation and complexity in biological systems. To investigate whether the evolution of protein-protein interface acts in a similar way as antibody affinity maturation, we incorporated evolutionary information derived from antibody affinity maturation with common simulation techniques to evaluate prediction success rates of the computational method in affinity improvement in four different systems: antibody-receptor, antibody-peptide, receptor-membrane ligand, and receptor-soluble ligand. It was interesting to find that the same evolutionary information could improve the prediction success rates in all the four protein-protein complexes with an exceptional high accuracy (>57%). One of the most striking findings in our present study is that not only in the antibody-combining site but in other protein-protein interfaces almost all of the affinity-enhancing mutations are located at the germline hotspot sequences (RGYW or WA), indicating that DNA hot spot mechanisms may be widely used in the evolution of protein-protein interfaces. Our data suggest that the evolution of distinct protein-protein interfaces may use the same basic strategy under selection pressure to maintain interactions. Additionally, our data indicate that classical simulation techniques incorporating the evolutionary information derived from in vivo antibody affinity maturation can be utilized as a powerful tool to improve the binding affinity of protein-protein complex with a high accuracy. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.

Gao J.,International Medical University | Gao J.,National Engineering Research Center for Antibody Medicine | Chen H.,International Medical University | Yu Y.,International Medical University | And 16 more authors.
Biomaterials | Year: 2013

The chemotherapy combined with gene therapy has received great attention. We developed targeted LPD (liposome-polycation-DNA complex) conjugated with anti-EGFR (epidermal growth factor receptor) Fab' co-delivering adriamycin (ADR) and ribonucleotide reductase M2 (RRM2) siRNA (ADR-RRM2-TLPD), to achieve combined therapeutic effects in human hepatocellular carcinoma (HCC) overexpressing EGFR. The antitumor activity and mechanisms of ADR-RRM2-TLPD were investigated. The results showed that RRM2 expression was higher in HCC than in non-HCC tissue, and RRM2 siRNA inhibited HCC cell proliferation, suggesting that RRM2 is a candidate target for HCC therapy. ADR-RRM2-TLPD delivered ADR and RRM2 siRNA to EGFR overexpressing HCC cells specifically and efficiently both invitro and invivo, resulting in enhanced therapeutic effects (cytotoxicity, apoptosis and senescence-inducing activity) compared with single-drug loaded or non-targeted controls, including ADR-NC-TLPD (targeted LPD co-delivering ADR and negative control siRNA), RRM2-TLPD (targeted LPD delivering RRM2 siRNA) and ADR-RRM2-NTLPD (non-targeted LPD co-delivering ADR and RRM2 siRNA). Mechanism studies showed that p21 is involved in the combined therapeutic effect of ADR-RRM2-TLPD. The average weight of the orthotopic HCC in mice treated with ADR-RRM2-TLPD was significantly lighter than that of mice treated with other controls. Thus, ADR-RRM2-TLPD represents a potential strategy for combined therapy of HCC overexpressing EGFR. © 2013 Elsevier Ltd.

Gao J.,International Medical University | Gao J.,National Engineering Research Center for Antibody Medicine | Gao J.,Shanghai University College of Sciences | Sun J.,International Medical University | And 21 more authors.
Biomaterials | Year: 2010

The development of a tumor-specific immunoliposome delivering small interfering RNA (siRNA) represents a practical way in cancer gene therapy. In this study, we developed PEGylated 3β-[N-(N′, N′-dimethylaminoethane) carbamoyl] cholesterol (DC-Chol)/dioleoylphosphatidyl ethanolamine (DOPE) immunoliposomes conjugated with the Fab' of recombinant humanized anti-HER2 monoclonal antibody (PIL) for siRNA delivery. The results demonstrated that the lyophilized PIL (LPIL) prepared by the lyophilization/rehydration method possessed a significantly enhanced HER1 gene, a model target, silencing ability compared with PIL in HER2-overexpressing SK-BR3 cells. Among a series of LPIL with different PEGylation degree, LPIL containing 2.5%PEG (2.5%PEG LPIL) showed the best HER1 gene silencing activity. Confocal microscope studies demonstrated that 2.5%PEG LPIL could specifically bind to SK-BR3 cells and were sequentially internalized into them. Using RhoA as a cancer therapeutic target, 2.5%PEG LPIL entrapping anti-RhoA siRNA could specifically silence RhoA expression and inhibit cell invasion in SK-BR3 cells. In conclusion, these finding demonstrated the potential use of 2.5%PEG LPIL in specifically delivering siRNA to HER2-overexpressing cancers. © 2009 Elsevier Ltd. All rights reserved.

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