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Disulfide bond bridge insertion turns hydrophobic anticancer prodrugs into self-assembled nanomedicines.

Wang Y, Liu D, Zheng Q, Zhao Q, Zhang H, Ma Y, Fallon JK, Fu Q, Haynes MT, Lin G, Zhang R, Wang D, Yang X, Zhao L, He Z, Liu F - Nano Lett. (2014)

Bottom Line: It is commonly observed that hydrophobic molecules alone cannot self-assemble into stable nanoparticles, requiring amphiphilic or ionic materials to support nanoparticle stability and function in vivo.We present proof-of-concept methodology and results in support of our hypothesis that disulfide-induced nanomedicines (DSINMs) are promoted and stabilized by the insertion of a single disulfide bond into hydrophobic molecules, in order to balance the competition between intermolecular forces involved in the self-assembly of nanomedicines.Such an unprecedented and highly reproducible system has the potential to serve as a synthetic platform for a wide array of safe and effective therapeutic and diagnostic nanomedicine strategies.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.

ABSTRACT
It is commonly observed that hydrophobic molecules alone cannot self-assemble into stable nanoparticles, requiring amphiphilic or ionic materials to support nanoparticle stability and function in vivo. We report herein newly self-assembled nanomedicines through entirely different mechanisms. We present proof-of-concept methodology and results in support of our hypothesis that disulfide-induced nanomedicines (DSINMs) are promoted and stabilized by the insertion of a single disulfide bond into hydrophobic molecules, in order to balance the competition between intermolecular forces involved in the self-assembly of nanomedicines. This hypothesis has been explored through diverse synthetic compounds, which include four first-line chemotherapy drugs (paclitaxel, doxorubicin, fluorouracil, and gemcitabine), two small-molecule natural products and their derivatives, as well as a fluorescent probe. Such an unprecedented and highly reproducible system has the potential to serve as a synthetic platform for a wide array of safe and effective therapeutic and diagnostic nanomedicine strategies.

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Characterization of PEGylated DSINMs for their physical image,plasma concentrations, anticancer activity, toxicity and tumor imaging.(a) TEM image of PTX–S–S–VE DSINMs PEGylatedwith 15% (w/w) DSPE-PEG2000. (b) Plasma concentration profiles ofPEGylated and non-PEGylated PTX–S–S–VE DSINMscompared with Taxol (n = 3). (c) Antitumor effectsin mice models, ** p < 0.01 (Student’s t-test, paired, two sided), compared with Taxol group andsaline group (n = 5). (d) Kidney and liver functionparameters in PEGylated PTX–S–S–VE DSINM andsaline treated control groups (n = 5). (e) Tumorimaging in live mice. The tumor (indicated by arrows) bearing micewere imaged 2 and 4 h after injection of free SRB and PEGylated SRB–S–S–VEDSINMs. Images at 8, 12, and 48 h are shown in Supporting Information Figure S9.
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fig5: Characterization of PEGylated DSINMs for their physical image,plasma concentrations, anticancer activity, toxicity and tumor imaging.(a) TEM image of PTX–S–S–VE DSINMs PEGylatedwith 15% (w/w) DSPE-PEG2000. (b) Plasma concentration profiles ofPEGylated and non-PEGylated PTX–S–S–VE DSINMscompared with Taxol (n = 3). (c) Antitumor effectsin mice models, ** p < 0.01 (Student’s t-test, paired, two sided), compared with Taxol group andsaline group (n = 5). (d) Kidney and liver functionparameters in PEGylated PTX–S–S–VE DSINM andsaline treated control groups (n = 5). (e) Tumorimaging in live mice. The tumor (indicated by arrows) bearing micewere imaged 2 and 4 h after injection of free SRB and PEGylated SRB–S–S–VEDSINMs. Images at 8, 12, and 48 h are shown in Supporting Information Figure S9.

Mentions: PEGylation ofNPs provides an effective means to reduce clearanceby the reticuloendothelial system (RES).19 We, therefore, PEGylated DSINMs by mixing 15% (w/w) DSPE-PEG2000with PTX–S–S–VE DSINMs. TEM images clearly confirmedPEGylation of DSINMs (Figure 5a). The particlesize of PEGylated DSINMs was 124.9 nm (SupportingInformation Figure S2, last image), and ζ potential was−28.7 mV. To evaluate the behavior of the DSINMs in mice, thePTX–S–S–VE DSINMs with and without PEGylationwere administered systemically. Plasma concentration of PTX–S–S–VEwas measured as a function of time postinjection. The data was fittedto a noncompartmental pharmacokinetic model (Figure 5b and Supporting Information TableS2). Non-PEGylated DSINMs and Taxol were cleared rapidly from theblood. However, the circulation time of PEGylated DSINMs was greatlyimproved, yielding a terminal half-life (t1/2) of 25.74 ± 7.66 h compared to a t1/2 of 1.47 ± 0.16 h (p < 0.05, Student’s t-test, paired, two sided) for Taxol. The AUC0–t values of PEGylated PTX–S–S–VEDSINMs were 250-fold higher than those of Taxol (p < 0.01, Student’s t-test, paired, twosided). Altered biodistribution profiles of PEGylated DOX–S–S–SADSINMs provide additional information that PEGylation can improvethe blood retention of DSINMs (Supporting Information Figure S5). All these results suggested that the PEGylated DSINMsmay be likely to preferentially accumulate in solid tumors to a greaterextent than Taxol via the enhanced permeability and retention (EPR)effect.


Disulfide bond bridge insertion turns hydrophobic anticancer prodrugs into self-assembled nanomedicines.

Wang Y, Liu D, Zheng Q, Zhao Q, Zhang H, Ma Y, Fallon JK, Fu Q, Haynes MT, Lin G, Zhang R, Wang D, Yang X, Zhao L, He Z, Liu F - Nano Lett. (2014)

Characterization of PEGylated DSINMs for their physical image,plasma concentrations, anticancer activity, toxicity and tumor imaging.(a) TEM image of PTX–S–S–VE DSINMs PEGylatedwith 15% (w/w) DSPE-PEG2000. (b) Plasma concentration profiles ofPEGylated and non-PEGylated PTX–S–S–VE DSINMscompared with Taxol (n = 3). (c) Antitumor effectsin mice models, ** p < 0.01 (Student’s t-test, paired, two sided), compared with Taxol group andsaline group (n = 5). (d) Kidney and liver functionparameters in PEGylated PTX–S–S–VE DSINM andsaline treated control groups (n = 5). (e) Tumorimaging in live mice. The tumor (indicated by arrows) bearing micewere imaged 2 and 4 h after injection of free SRB and PEGylated SRB–S–S–VEDSINMs. Images at 8, 12, and 48 h are shown in Supporting Information Figure S9.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4334225&req=5

fig5: Characterization of PEGylated DSINMs for their physical image,plasma concentrations, anticancer activity, toxicity and tumor imaging.(a) TEM image of PTX–S–S–VE DSINMs PEGylatedwith 15% (w/w) DSPE-PEG2000. (b) Plasma concentration profiles ofPEGylated and non-PEGylated PTX–S–S–VE DSINMscompared with Taxol (n = 3). (c) Antitumor effectsin mice models, ** p < 0.01 (Student’s t-test, paired, two sided), compared with Taxol group andsaline group (n = 5). (d) Kidney and liver functionparameters in PEGylated PTX–S–S–VE DSINM andsaline treated control groups (n = 5). (e) Tumorimaging in live mice. The tumor (indicated by arrows) bearing micewere imaged 2 and 4 h after injection of free SRB and PEGylated SRB–S–S–VEDSINMs. Images at 8, 12, and 48 h are shown in Supporting Information Figure S9.
Mentions: PEGylation ofNPs provides an effective means to reduce clearanceby the reticuloendothelial system (RES).19 We, therefore, PEGylated DSINMs by mixing 15% (w/w) DSPE-PEG2000with PTX–S–S–VE DSINMs. TEM images clearly confirmedPEGylation of DSINMs (Figure 5a). The particlesize of PEGylated DSINMs was 124.9 nm (SupportingInformation Figure S2, last image), and ζ potential was−28.7 mV. To evaluate the behavior of the DSINMs in mice, thePTX–S–S–VE DSINMs with and without PEGylationwere administered systemically. Plasma concentration of PTX–S–S–VEwas measured as a function of time postinjection. The data was fittedto a noncompartmental pharmacokinetic model (Figure 5b and Supporting Information TableS2). Non-PEGylated DSINMs and Taxol were cleared rapidly from theblood. However, the circulation time of PEGylated DSINMs was greatlyimproved, yielding a terminal half-life (t1/2) of 25.74 ± 7.66 h compared to a t1/2 of 1.47 ± 0.16 h (p < 0.05, Student’s t-test, paired, two sided) for Taxol. The AUC0–t values of PEGylated PTX–S–S–VEDSINMs were 250-fold higher than those of Taxol (p < 0.01, Student’s t-test, paired, twosided). Altered biodistribution profiles of PEGylated DOX–S–S–SADSINMs provide additional information that PEGylation can improvethe blood retention of DSINMs (Supporting Information Figure S5). All these results suggested that the PEGylated DSINMsmay be likely to preferentially accumulate in solid tumors to a greaterextent than Taxol via the enhanced permeability and retention (EPR)effect.

Bottom Line: It is commonly observed that hydrophobic molecules alone cannot self-assemble into stable nanoparticles, requiring amphiphilic or ionic materials to support nanoparticle stability and function in vivo.We present proof-of-concept methodology and results in support of our hypothesis that disulfide-induced nanomedicines (DSINMs) are promoted and stabilized by the insertion of a single disulfide bond into hydrophobic molecules, in order to balance the competition between intermolecular forces involved in the self-assembly of nanomedicines.Such an unprecedented and highly reproducible system has the potential to serve as a synthetic platform for a wide array of safe and effective therapeutic and diagnostic nanomedicine strategies.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.

ABSTRACT
It is commonly observed that hydrophobic molecules alone cannot self-assemble into stable nanoparticles, requiring amphiphilic or ionic materials to support nanoparticle stability and function in vivo. We report herein newly self-assembled nanomedicines through entirely different mechanisms. We present proof-of-concept methodology and results in support of our hypothesis that disulfide-induced nanomedicines (DSINMs) are promoted and stabilized by the insertion of a single disulfide bond into hydrophobic molecules, in order to balance the competition between intermolecular forces involved in the self-assembly of nanomedicines. This hypothesis has been explored through diverse synthetic compounds, which include four first-line chemotherapy drugs (paclitaxel, doxorubicin, fluorouracil, and gemcitabine), two small-molecule natural products and their derivatives, as well as a fluorescent probe. Such an unprecedented and highly reproducible system has the potential to serve as a synthetic platform for a wide array of safe and effective therapeutic and diagnostic nanomedicine strategies.

Show MeSH
Related in: MedlinePlus