Wenchen Zhao | University of Pittsburgh (original) (raw)
Papers by Wenchen Zhao
Bioconjugate Chemistry, 2013
S-trans, trans-farnesylthiosalicylic acid (FTS) is a synthetic small molecule that acts as a pote... more S-trans, trans-farnesylthiosalicylic acid (FTS) is a synthetic small molecule that acts as a potent and especially nontoxic Ras antagonist. It inhibits both oncogenically activated Ras and growth factor receptor-mediated Ras activation, resulting in the inhibition of Ras-dependent tumor growth. In this work, a FTS conjugate with polyethylene glycol (PEG) through a labile ester linkage, PEG 5K-FTS 2 (L), was developed. PEG 5K-FTS 2 conjugate readily forms micelles in aqueous solutions with a critical micelle concentration of 0.68 μM and hydrophobic drugs such as paclitaxel (PTX) could be effectively loaded into these particles. Both drug-free and PTX-loaded micelles were spherical in shape with a uniform size of 20 ~ 30 nm. The release of PTX from PTX-loaded PEG 5K-FTS 2 micelles was significantly slower than that from Taxol formulation. In vitro cytotoxicity studies with several tumor cell lines showed that PEG 5K-FTS 2 (L) was comparable to FTS in antitumor activity. Western immunoblotting showed that total Ras levels were downregulated in several cancer cell lines treated with FTS or PEG 5K-FTS 2 (L). The micellar formulation of PTX exhibited more in vitro cytotoxic activity against several tumor cell lines compared with free PTX, suggesting a possible synergistic effect between the carrier and the codelivered drug. The anti-tumor activity of the PTX loaded PEG 5K-FTS 2 (L) micelles in a syngeneic murine breast cancer model was found to be significantly higher than that of Taxol, which may be attributed to their preferential tumor accumulation and a possible synergistic effect between PEG 5K-FTS 2 carrier and loaded PTX.
Nature communications, Nov 7, 2016
Immunochemotherapy combines a chemotherapeutic agent with an immune-modulating agent and represen... more Immunochemotherapy combines a chemotherapeutic agent with an immune-modulating agent and represents an attractive approach to improve cancer therapy. However, the success of immunochemotherapy is hampered by the lack of a strategy to effectively co-deliver the two therapeutics to the tumours. Here we report the development of a dual-functional, immunostimulatory nanomicellar carrier that is based on a prodrug conjugate of PEG with NLG919, an indoleamine 2,3-dioxygenase (IDO) inhibitor currently used for reversing tumour immune suppression. An Fmoc group, an effective drug-interactive motif, is also introduced into the carrier to improve the drug loading capacity and formulation stability. We show that PEG2k-Fmoc-NLG alone is effective in enhancing T-cell immune responses and exhibits significant antitumour activity in vivo. More importantly, systemic delivery of paclitaxel (PTX) using the PEG2k-Fmoc-NLG nanocarrier leads to a significantly improved antitumour response in both breast...
A simple and sensitive method for evaluating the chemical compositions of protein amino acids, in... more A simple and sensitive method for evaluating the chemical compositions of protein amino acids, including cystine (Cys) 2 and tryptophane (Try) has been developed, based on the use of a sensitive labeling reagent 2-(11Hbenzo[α]-carbazol-11-yl) ethyl chloroformate (BCEC-Cl) along with fluorescence detection. The chromophore of the 1,2-benzo-3,4-dihydrocarbazole-ethyl chloroformate (BCEOC-Cl) molecule was replaced with the 2-(11Hbenzo[α]-carbazol-11-yl) ethyl functional group, yielding the sensitive fluorescence molecule BCEC-Cl. The new reagent BCEC-Cl could then be substituted for labeling reagents commonly used in amino acid derivatization. The BCEC-amino acid derivatives exhibited very high detection sensitivities, particularly in the cases of (Cys) 2 and Try, which cannot be determined using traditional labeling reagents such as 9-fluorenyl methylchloroformate (FMOC-Cl) and ortho-phthaldialdehyde (OPA). The fluorescence detection intensities for the BCEC derivatives were compared to those obtained when using FMOC-Cl and BCEOC-Cl as labeling reagents. The ratios I BCEC / I BCEOC =1.17-3.57, I BCEC /I FMOC =1.13-8.21, and UV BCEC / UV BCEOC =1.67-4.90 (where I is the fluorescence intensity and UV is the ultraviolet absorbance). Derivative separation was optimized on a Hypersil BDS C 18 column. The detection limits calculated from 1.0 pmol injections, at a signal-to-noise ratio of 3, ranged from 7.2 fmol for Try to 8.4 fmol for (Cys) 2 . Excellent linear responses were observed, with coefficients of >0.9994. When coupled with high-performance liquid chromatography, the method established here allowed the development of a highly sensitive and specific method for the quantitative analysis of trace levels of amino acids including (Cys) 2 and Try from bee-collected pollen (bee pollen) samples.
Bioconjugate Chemistry, 2013
S-trans, trans-farnesylthiosalicylic acid (FTS) is a synthetic small molecule that acts as a pote... more S-trans, trans-farnesylthiosalicylic acid (FTS) is a synthetic small molecule that acts as a potent and especially nontoxic Ras antagonist. It inhibits both oncogenically activated Ras and growth factor receptor-mediated Ras activation, resulting in the inhibition of Ras-dependent tumor growth. In this work, a FTS conjugate with polyethylene glycol (PEG) through a labile ester linkage, PEG 5K-FTS 2 (L), was developed. PEG 5K-FTS 2 conjugate readily forms micelles in aqueous solutions with a critical micelle concentration of 0.68 μM and hydrophobic drugs such as paclitaxel (PTX) could be effectively loaded into these particles. Both drug-free and PTX-loaded micelles were spherical in shape with a uniform size of 20 ~ 30 nm. The release of PTX from PTX-loaded PEG 5K-FTS 2 micelles was significantly slower than that from Taxol formulation. In vitro cytotoxicity studies with several tumor cell lines showed that PEG 5K-FTS 2 (L) was comparable to FTS in antitumor activity. Western immunoblotting showed that total Ras levels were downregulated in several cancer cell lines treated with FTS or PEG 5K-FTS 2 (L). The micellar formulation of PTX exhibited more in vitro cytotoxic activity against several tumor cell lines compared with free PTX, suggesting a possible synergistic effect between the carrier and the codelivered drug. The anti-tumor activity of the PTX loaded PEG 5K-FTS 2 (L) micelles in a syngeneic murine breast cancer model was found to be significantly higher than that of Taxol, which may be attributed to their preferential tumor accumulation and a possible synergistic effect between PEG 5K-FTS 2 carrier and loaded PTX.
Nature communications, Nov 7, 2016
Immunochemotherapy combines a chemotherapeutic agent with an immune-modulating agent and represen... more Immunochemotherapy combines a chemotherapeutic agent with an immune-modulating agent and represents an attractive approach to improve cancer therapy. However, the success of immunochemotherapy is hampered by the lack of a strategy to effectively co-deliver the two therapeutics to the tumours. Here we report the development of a dual-functional, immunostimulatory nanomicellar carrier that is based on a prodrug conjugate of PEG with NLG919, an indoleamine 2,3-dioxygenase (IDO) inhibitor currently used for reversing tumour immune suppression. An Fmoc group, an effective drug-interactive motif, is also introduced into the carrier to improve the drug loading capacity and formulation stability. We show that PEG2k-Fmoc-NLG alone is effective in enhancing T-cell immune responses and exhibits significant antitumour activity in vivo. More importantly, systemic delivery of paclitaxel (PTX) using the PEG2k-Fmoc-NLG nanocarrier leads to a significantly improved antitumour response in both breast...
A simple and sensitive method for evaluating the chemical compositions of protein amino acids, in... more A simple and sensitive method for evaluating the chemical compositions of protein amino acids, including cystine (Cys) 2 and tryptophane (Try) has been developed, based on the use of a sensitive labeling reagent 2-(11Hbenzo[α]-carbazol-11-yl) ethyl chloroformate (BCEC-Cl) along with fluorescence detection. The chromophore of the 1,2-benzo-3,4-dihydrocarbazole-ethyl chloroformate (BCEOC-Cl) molecule was replaced with the 2-(11Hbenzo[α]-carbazol-11-yl) ethyl functional group, yielding the sensitive fluorescence molecule BCEC-Cl. The new reagent BCEC-Cl could then be substituted for labeling reagents commonly used in amino acid derivatization. The BCEC-amino acid derivatives exhibited very high detection sensitivities, particularly in the cases of (Cys) 2 and Try, which cannot be determined using traditional labeling reagents such as 9-fluorenyl methylchloroformate (FMOC-Cl) and ortho-phthaldialdehyde (OPA). The fluorescence detection intensities for the BCEC derivatives were compared to those obtained when using FMOC-Cl and BCEOC-Cl as labeling reagents. The ratios I BCEC / I BCEOC =1.17-3.57, I BCEC /I FMOC =1.13-8.21, and UV BCEC / UV BCEOC =1.67-4.90 (where I is the fluorescence intensity and UV is the ultraviolet absorbance). Derivative separation was optimized on a Hypersil BDS C 18 column. The detection limits calculated from 1.0 pmol injections, at a signal-to-noise ratio of 3, ranged from 7.2 fmol for Try to 8.4 fmol for (Cys) 2 . Excellent linear responses were observed, with coefficients of >0.9994. When coupled with high-performance liquid chromatography, the method established here allowed the development of a highly sensitive and specific method for the quantitative analysis of trace levels of amino acids including (Cys) 2 and Try from bee-collected pollen (bee pollen) samples.