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Self-assembled micellar nanocomplexes comprising green tea catechin derivatives and protein drugs for cancer therapy.

Chung JE, Tan S, Gao SJ, Yongvongsoontorn N, Kim SH, Lee JH, Choi HS, Yano H, Zhuo L, Kurisawa M, Ying JY - Nat Nanotechnol (2014)

Bottom Line: However, these issues would be of less concern if both the drug and carrier had therapeutic effects. (-)-Epigallocatechin-3-O-gallate (EGCG), a major ingredient of green tea, has been shown, for example, to possess anticancer effects, anti-HIV effects, neuroprotective effects and DNA-protective effects.Here, we show that sequential self-assembly of the EGCG derivative with anticancer proteins leads to the formation of stable micellar nanocomplexes, which have greater anticancer effects in vitro and in vivo than the free protein.The micellar nanocomplex is obtained by complexation of oligomerized EGCG with the anticancer protein Herceptin to form the core, followed by complexation of poly(ethylene glycol)-EGCG to form the shell.

View Article: PubMed Central - PubMed

Affiliation: Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, 138669 Singapore.

ABSTRACT
When designing drug carriers, the drug-to-carrier ratio is an important consideration, because the use of high quantities of carriers can result in toxicity as a consequence of poor metabolism and elimination of the carriers. However, these issues would be of less concern if both the drug and carrier had therapeutic effects. (-)-Epigallocatechin-3-O-gallate (EGCG), a major ingredient of green tea, has been shown, for example, to possess anticancer effects, anti-HIV effects, neuroprotective effects and DNA-protective effects. Here, we show that sequential self-assembly of the EGCG derivative with anticancer proteins leads to the formation of stable micellar nanocomplexes, which have greater anticancer effects in vitro and in vivo than the free protein. The micellar nanocomplex is obtained by complexation of oligomerized EGCG with the anticancer protein Herceptin to form the core, followed by complexation of poly(ethylene glycol)-EGCG to form the shell. When injected into mice, the Herceptin-loaded micellar nanocomplex demonstrates better tumour selectivity and growth reduction, as well as longer blood half-life, than free Herceptin.

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The core-shell MNC formationa, Complex size obtained when PEG-EGCG of various concentrations was added to the pre-formed Herceptin/OEGCG complexes (OEGCG = 0.09 μg ml−1 (white circles), 3 μg ml−1 (white squares), 6 μg ml−1 (white triangles) and 12 μg ml−1 (black circles)). PEG-EGCG assembled around the Herceptin/OEGCG complex of varied sizes, yielding uniformly sized complexes at the critical PEG-EGCG concentration required. The uniform size remained constant, despite further increase in the PEG-EGCG concentration. The data points represent mean values and the bars represent s.d. (n = 3). b, Complexes formed with various compositions and adding sequences. The sequential two-step self-assembly (the assembly of OEGCG with Herceptin followed by the PEG-EGCG assembly around the Herceptin/OEGCG complex) was necessary to construct the stable and spatially ordered MNC that showed no change in size by the post-addition of Herceptin. The results are reported as mean values and the bars represent s.d. (n = 3).
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Figure 3: The core-shell MNC formationa, Complex size obtained when PEG-EGCG of various concentrations was added to the pre-formed Herceptin/OEGCG complexes (OEGCG = 0.09 μg ml−1 (white circles), 3 μg ml−1 (white squares), 6 μg ml−1 (white triangles) and 12 μg ml−1 (black circles)). PEG-EGCG assembled around the Herceptin/OEGCG complex of varied sizes, yielding uniformly sized complexes at the critical PEG-EGCG concentration required. The uniform size remained constant, despite further increase in the PEG-EGCG concentration. The data points represent mean values and the bars represent s.d. (n = 3). b, Complexes formed with various compositions and adding sequences. The sequential two-step self-assembly (the assembly of OEGCG with Herceptin followed by the PEG-EGCG assembly around the Herceptin/OEGCG complex) was necessary to construct the stable and spatially ordered MNC that showed no change in size by the post-addition of Herceptin. The results are reported as mean values and the bars represent s.d. (n = 3).

Mentions: In order to construct the outer shell surrounding the core complex, PEG-EGCG was added to the pre-formed Herceptin/OEGCG complexes. When PEG-EGCG was added in increasing amounts to the Herceptin/OEGCG complexes of varied sizes, complexes were formed with a uniform size that remained constant, despite further increase in the PEG-EGCG concentration (Fig. 3a). TEM images showed that at increasing OEGCG concentration, the increase in the average size of Herceptin/OEGCG complex is due to increasing numbers of pre-existing Herceptin/OEGCG complexes that are complexing with each other, rather than an increase in the diameter of the pre-existing complexes (Supplementary Information, Fig. S5). This phenomenon has been known in the mechanism for polyphenol/protein complexation that the pre-existing complexes are associated by bridging through polyphenols, when the polyphenol concentration is increased28. The inter-complex association between Herceptin/OEGCG complexes was likely dissociated by PEG-EGCG due to hydrophobic competition with the EGCG moieties of PEG-EGCG. Subsequently, PEG-EGCG assembled around the Herceptin/OEGCG complex at the critical PEG-EGCG concentration required, yielding uniformly sized complexes under favourably balanced interaction energy. The constant complex size above the critical PEG-EGCG concentration could be due to repulsion against further assembly by the PEG outer shell that was formed.


Self-assembled micellar nanocomplexes comprising green tea catechin derivatives and protein drugs for cancer therapy.

Chung JE, Tan S, Gao SJ, Yongvongsoontorn N, Kim SH, Lee JH, Choi HS, Yano H, Zhuo L, Kurisawa M, Ying JY - Nat Nanotechnol (2014)

The core-shell MNC formationa, Complex size obtained when PEG-EGCG of various concentrations was added to the pre-formed Herceptin/OEGCG complexes (OEGCG = 0.09 μg ml−1 (white circles), 3 μg ml−1 (white squares), 6 μg ml−1 (white triangles) and 12 μg ml−1 (black circles)). PEG-EGCG assembled around the Herceptin/OEGCG complex of varied sizes, yielding uniformly sized complexes at the critical PEG-EGCG concentration required. The uniform size remained constant, despite further increase in the PEG-EGCG concentration. The data points represent mean values and the bars represent s.d. (n = 3). b, Complexes formed with various compositions and adding sequences. The sequential two-step self-assembly (the assembly of OEGCG with Herceptin followed by the PEG-EGCG assembly around the Herceptin/OEGCG complex) was necessary to construct the stable and spatially ordered MNC that showed no change in size by the post-addition of Herceptin. The results are reported as mean values and the bars represent s.d. (n = 3).
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Related In: Results  -  Collection

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Figure 3: The core-shell MNC formationa, Complex size obtained when PEG-EGCG of various concentrations was added to the pre-formed Herceptin/OEGCG complexes (OEGCG = 0.09 μg ml−1 (white circles), 3 μg ml−1 (white squares), 6 μg ml−1 (white triangles) and 12 μg ml−1 (black circles)). PEG-EGCG assembled around the Herceptin/OEGCG complex of varied sizes, yielding uniformly sized complexes at the critical PEG-EGCG concentration required. The uniform size remained constant, despite further increase in the PEG-EGCG concentration. The data points represent mean values and the bars represent s.d. (n = 3). b, Complexes formed with various compositions and adding sequences. The sequential two-step self-assembly (the assembly of OEGCG with Herceptin followed by the PEG-EGCG assembly around the Herceptin/OEGCG complex) was necessary to construct the stable and spatially ordered MNC that showed no change in size by the post-addition of Herceptin. The results are reported as mean values and the bars represent s.d. (n = 3).
Mentions: In order to construct the outer shell surrounding the core complex, PEG-EGCG was added to the pre-formed Herceptin/OEGCG complexes. When PEG-EGCG was added in increasing amounts to the Herceptin/OEGCG complexes of varied sizes, complexes were formed with a uniform size that remained constant, despite further increase in the PEG-EGCG concentration (Fig. 3a). TEM images showed that at increasing OEGCG concentration, the increase in the average size of Herceptin/OEGCG complex is due to increasing numbers of pre-existing Herceptin/OEGCG complexes that are complexing with each other, rather than an increase in the diameter of the pre-existing complexes (Supplementary Information, Fig. S5). This phenomenon has been known in the mechanism for polyphenol/protein complexation that the pre-existing complexes are associated by bridging through polyphenols, when the polyphenol concentration is increased28. The inter-complex association between Herceptin/OEGCG complexes was likely dissociated by PEG-EGCG due to hydrophobic competition with the EGCG moieties of PEG-EGCG. Subsequently, PEG-EGCG assembled around the Herceptin/OEGCG complex at the critical PEG-EGCG concentration required, yielding uniformly sized complexes under favourably balanced interaction energy. The constant complex size above the critical PEG-EGCG concentration could be due to repulsion against further assembly by the PEG outer shell that was formed.

Bottom Line: However, these issues would be of less concern if both the drug and carrier had therapeutic effects. (-)-Epigallocatechin-3-O-gallate (EGCG), a major ingredient of green tea, has been shown, for example, to possess anticancer effects, anti-HIV effects, neuroprotective effects and DNA-protective effects.Here, we show that sequential self-assembly of the EGCG derivative with anticancer proteins leads to the formation of stable micellar nanocomplexes, which have greater anticancer effects in vitro and in vivo than the free protein.The micellar nanocomplex is obtained by complexation of oligomerized EGCG with the anticancer protein Herceptin to form the core, followed by complexation of poly(ethylene glycol)-EGCG to form the shell.

View Article: PubMed Central - PubMed

Affiliation: Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, 138669 Singapore.

ABSTRACT
When designing drug carriers, the drug-to-carrier ratio is an important consideration, because the use of high quantities of carriers can result in toxicity as a consequence of poor metabolism and elimination of the carriers. However, these issues would be of less concern if both the drug and carrier had therapeutic effects. (-)-Epigallocatechin-3-O-gallate (EGCG), a major ingredient of green tea, has been shown, for example, to possess anticancer effects, anti-HIV effects, neuroprotective effects and DNA-protective effects. Here, we show that sequential self-assembly of the EGCG derivative with anticancer proteins leads to the formation of stable micellar nanocomplexes, which have greater anticancer effects in vitro and in vivo than the free protein. The micellar nanocomplex is obtained by complexation of oligomerized EGCG with the anticancer protein Herceptin to form the core, followed by complexation of poly(ethylene glycol)-EGCG to form the shell. When injected into mice, the Herceptin-loaded micellar nanocomplex demonstrates better tumour selectivity and growth reduction, as well as longer blood half-life, than free Herceptin.

Show MeSH
Related in: MedlinePlus