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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: 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.

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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Schematic diagram and morphology of self-assembled MNC loaded with proteinsa, Schematic diagram of the self-assembly process to form the MNC. The MNC was formed through two sequential self-assemblies in an aqueous solution: Complexation of OEGCG with proteins to form the core followed by complexation of PEG-EGCG surrounding the pre-formed core to form the shell. b, TEM images and c, hydrodynamic size distributions of complexes observed at each step of self-assembly.
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Figure 1: Schematic diagram and morphology of self-assembled MNC loaded with proteinsa, Schematic diagram of the self-assembly process to form the MNC. The MNC was formed through two sequential self-assemblies in an aqueous solution: Complexation of OEGCG with proteins to form the core followed by complexation of PEG-EGCG surrounding the pre-formed core to form the shell. b, TEM images and c, hydrodynamic size distributions of complexes observed at each step of self-assembly.

Mentions: Many macromolecular drug carriers have been significantly improved to alter the pharmacokinetics and biodistribution of drugs11-23, wherein the carrier is just an excipient for drug delivery and the therapeutically relevant compound is just the drug. We were inspired to design an improved delivery system whereby the carrier would display therapeutic effects. This was achieved by utilizing the binding property of EGCG with various biological molecules including proteins24, 25. We synthesized a MNC carrier comprised of two EGCG derivatives designed to bind with proteins in a spatially ordered structure. One of them was oligomerized EGCG (OEGCG), which was designed to stabilize the core by strengthening the binding property of EGCG with protein26. The other derivative was poly(ethylene glycol)-EGCG (PEG-EGCG), which was tailored to bind with the protein/OEGCG complex as an inert and hydrophilic shell with extended PEG chains. The MNC was formed through two sequential self-assemblies in an aqueous solution: (i) the complexation between OEGCG and proteins to form the core, and (ii) the complexation of PEG-EGCG surrounding the pre-formed core to form the shell (Fig. 1a). The micellar structure with PEG shell could reduce protein immunogenicity, and prevent rapid renal clearance and proteolysis of protein, decreasing the need for frequent injections or infusion therapy16, 21. Although many studies have discussed the beneficial bioactivities of EGCG, in this work, we attempted to utilize EGCG as a carrier for biological molecules, aiming at combinational therapeutic effects between the carrier and the drug.


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)

Schematic diagram and morphology of self-assembled MNC loaded with proteinsa, Schematic diagram of the self-assembly process to form the MNC. The MNC was formed through two sequential self-assemblies in an aqueous solution: Complexation of OEGCG with proteins to form the core followed by complexation of PEG-EGCG surrounding the pre-formed core to form the shell. b, TEM images and c, hydrodynamic size distributions of complexes observed at each step of self-assembly.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4221637&req=5

Figure 1: Schematic diagram and morphology of self-assembled MNC loaded with proteinsa, Schematic diagram of the self-assembly process to form the MNC. The MNC was formed through two sequential self-assemblies in an aqueous solution: Complexation of OEGCG with proteins to form the core followed by complexation of PEG-EGCG surrounding the pre-formed core to form the shell. b, TEM images and c, hydrodynamic size distributions of complexes observed at each step of self-assembly.
Mentions: Many macromolecular drug carriers have been significantly improved to alter the pharmacokinetics and biodistribution of drugs11-23, wherein the carrier is just an excipient for drug delivery and the therapeutically relevant compound is just the drug. We were inspired to design an improved delivery system whereby the carrier would display therapeutic effects. This was achieved by utilizing the binding property of EGCG with various biological molecules including proteins24, 25. We synthesized a MNC carrier comprised of two EGCG derivatives designed to bind with proteins in a spatially ordered structure. One of them was oligomerized EGCG (OEGCG), which was designed to stabilize the core by strengthening the binding property of EGCG with protein26. The other derivative was poly(ethylene glycol)-EGCG (PEG-EGCG), which was tailored to bind with the protein/OEGCG complex as an inert and hydrophilic shell with extended PEG chains. The MNC was formed through two sequential self-assemblies in an aqueous solution: (i) the complexation between OEGCG and proteins to form the core, and (ii) the complexation of PEG-EGCG surrounding the pre-formed core to form the shell (Fig. 1a). The micellar structure with PEG shell could reduce protein immunogenicity, and prevent rapid renal clearance and proteolysis of protein, decreasing the need for frequent injections or infusion therapy16, 21. Although many studies have discussed the beneficial bioactivities of EGCG, in this work, we attempted to utilize EGCG as a carrier for biological molecules, aiming at combinational therapeutic effects between the carrier and the drug.

Bottom Line: 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.

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