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Ultrasound-targeted stromal cell-derived factor-1-loaded microbubble destruction promotes mesenchymal stem cell homing to kidneys in diabetic nephropathy rats.

Wu S, Li L, Wang G, Shen W, Xu Y, Liu Z, Zhuo Z, Xia H, Gao Y, Tan K - Int J Nanomedicine (2014)

Bottom Line: The related bioeffects were also elucidated.In the in vivo study, SDF-1 was successfully released in the targeted kidneys.In conclusion, ultrasound-targeted MB(SDF-1) destruction could promote the homing of MSCs to early DN kidneys and provide a novel potential therapeutic approach for DN kidney repair.

View Article: PubMed Central - PubMed

Affiliation: Department of Ultrasound, Third Military Medical University, Chongqing, People's Republic of China.

ABSTRACT
Mesenchymal stem cell (MSC) therapy has been considered a promising strategy to cure diabetic nephropathy (DN). However, insufficient MSCs can settle in injured kidneys, which constitute one of the major barriers to the effective implementation of MSC therapy. Stromal cell-derived factor-1 (SDF-1) plays a vital role in MSC migration and involves activation, mobilization, homing, and retention, which are presumably related to the poor homing in DN therapy. Ultrasound-targeted microbubble destruction has become one of the most promising strategies for the targeted delivery of drugs and genes. To improve MSC homing to DN kidneys, we present a strategy to increase SDF-1 via ultrasound-targeted microbubble destruction. In this study, we developed SDF-1-loaded microbubbles (MB(SDF-1)) via covalent conjugation. The characterization and bioactivity of MB(SDF-1) were assessed in vitro. Target release in the targeted kidneys was triggered with diagnostic ultrasound in combination with MB(SDF-1). The related bioeffects were also elucidated. Early DN was induced in rats with streptozotocin. Green fluorescent protein-labeled MSCs were transplanted intravenously following the target release of SDF-1 in the kidneys of normal and DN rats. The homing efficacy was assessed by detecting the implanted exogenous MSCs at 24 hours. The in vitro results showed an impressive SDF-1 loading efficacy of 79% and a loading content of 15.8 μg/mL. MB(SDF-1) remained bioactive as a chemoattractant. In the in vivo study, SDF-1 was successfully released in the targeted kidneys. The homing efficacy of MSCs to DN kidneys after the target release of SDF-1 was remarkably ameliorated at 24 hours compared with control treatments in normal rats and DN rats. In conclusion, ultrasound-targeted MB(SDF-1) destruction could promote the homing of MSCs to early DN kidneys and provide a novel potential therapeutic approach for DN kidney repair.

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Schematic diagram of the preparation of MBSDF-1.Notes: The COOH groups in the COOH-PEG-COOH were activated by EDC/sulfo-NHS and then conjugated with SDF-1 via amide linkages. Finally, the lipid mixture with the conjugated product was vibrated with perfluoropropane (C3F8) to form the MBSDF-1.Abbreviations: MBSDF-1, SDF-1-loaded microbubbles; PEG, polyethylene glycol; EDC, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; sulfo-NHS, N-hydroxysulfosuccinimide sodium salt; SDF-1, stromal cell-derived factor-1; PEG-SDF-1, PEG-modulated SDF-1.
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f1-ijn-9-5639: Schematic diagram of the preparation of MBSDF-1.Notes: The COOH groups in the COOH-PEG-COOH were activated by EDC/sulfo-NHS and then conjugated with SDF-1 via amide linkages. Finally, the lipid mixture with the conjugated product was vibrated with perfluoropropane (C3F8) to form the MBSDF-1.Abbreviations: MBSDF-1, SDF-1-loaded microbubbles; PEG, polyethylene glycol; EDC, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; sulfo-NHS, N-hydroxysulfosuccinimide sodium salt; SDF-1, stromal cell-derived factor-1; PEG-SDF-1, PEG-modulated SDF-1.

Mentions: To obtain MBSDF-1, SDF-1 was firmly cross-linked with COOH-PEG4000-COOH via covalent conjugation using EDC/sulfo-NHS as coupling agents. The COOH groups of COOH-PEG4000-COOH were activated with EDC/sulfo-NHS. Briefly, EDC (5 μL, 50 mg/mL) and sulfo-NHS (5 μL, 100 mg/mL) were added to the unloaded MB solution mentioned earlier for 15 minutes at room temperature. Subsequently, 20 μL of SDF-1 solution (20 μg SDF-1 dissolved in 20 μL of water) was added and allowed to react with the activated COOH groups for 2 hours at room temperature. The resultant solution was treated following the same protocol as that used for unloaded MBs to form the primary MBSDF-1 (Figure 1). After washing with phosphate-buffered saline (PBS) and centrifugation at 1,000 rpm for 5 minutes, they were separated into two layers. The clear underlayer solution was discarded, by which the free SDF-1 (not loaded to the MBs) as well as the coupling agents were separated and removed. The milky suspension was acquired and the MBSDF-1 was ultimately obtained. The SDF-1 lipid solution was obtained after the sonication of MBSDF-1 to further characterize the MBs and conduct a cell migration assay.


Ultrasound-targeted stromal cell-derived factor-1-loaded microbubble destruction promotes mesenchymal stem cell homing to kidneys in diabetic nephropathy rats.

Wu S, Li L, Wang G, Shen W, Xu Y, Liu Z, Zhuo Z, Xia H, Gao Y, Tan K - Int J Nanomedicine (2014)

Schematic diagram of the preparation of MBSDF-1.Notes: The COOH groups in the COOH-PEG-COOH were activated by EDC/sulfo-NHS and then conjugated with SDF-1 via amide linkages. Finally, the lipid mixture with the conjugated product was vibrated with perfluoropropane (C3F8) to form the MBSDF-1.Abbreviations: MBSDF-1, SDF-1-loaded microbubbles; PEG, polyethylene glycol; EDC, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; sulfo-NHS, N-hydroxysulfosuccinimide sodium salt; SDF-1, stromal cell-derived factor-1; PEG-SDF-1, PEG-modulated SDF-1.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4263441&req=5

f1-ijn-9-5639: Schematic diagram of the preparation of MBSDF-1.Notes: The COOH groups in the COOH-PEG-COOH were activated by EDC/sulfo-NHS and then conjugated with SDF-1 via amide linkages. Finally, the lipid mixture with the conjugated product was vibrated with perfluoropropane (C3F8) to form the MBSDF-1.Abbreviations: MBSDF-1, SDF-1-loaded microbubbles; PEG, polyethylene glycol; EDC, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide; sulfo-NHS, N-hydroxysulfosuccinimide sodium salt; SDF-1, stromal cell-derived factor-1; PEG-SDF-1, PEG-modulated SDF-1.
Mentions: To obtain MBSDF-1, SDF-1 was firmly cross-linked with COOH-PEG4000-COOH via covalent conjugation using EDC/sulfo-NHS as coupling agents. The COOH groups of COOH-PEG4000-COOH were activated with EDC/sulfo-NHS. Briefly, EDC (5 μL, 50 mg/mL) and sulfo-NHS (5 μL, 100 mg/mL) were added to the unloaded MB solution mentioned earlier for 15 minutes at room temperature. Subsequently, 20 μL of SDF-1 solution (20 μg SDF-1 dissolved in 20 μL of water) was added and allowed to react with the activated COOH groups for 2 hours at room temperature. The resultant solution was treated following the same protocol as that used for unloaded MBs to form the primary MBSDF-1 (Figure 1). After washing with phosphate-buffered saline (PBS) and centrifugation at 1,000 rpm for 5 minutes, they were separated into two layers. The clear underlayer solution was discarded, by which the free SDF-1 (not loaded to the MBs) as well as the coupling agents were separated and removed. The milky suspension was acquired and the MBSDF-1 was ultimately obtained. The SDF-1 lipid solution was obtained after the sonication of MBSDF-1 to further characterize the MBs and conduct a cell migration assay.

Bottom Line: The related bioeffects were also elucidated.In the in vivo study, SDF-1 was successfully released in the targeted kidneys.In conclusion, ultrasound-targeted MB(SDF-1) destruction could promote the homing of MSCs to early DN kidneys and provide a novel potential therapeutic approach for DN kidney repair.

View Article: PubMed Central - PubMed

Affiliation: Department of Ultrasound, Third Military Medical University, Chongqing, People's Republic of China.

ABSTRACT
Mesenchymal stem cell (MSC) therapy has been considered a promising strategy to cure diabetic nephropathy (DN). However, insufficient MSCs can settle in injured kidneys, which constitute one of the major barriers to the effective implementation of MSC therapy. Stromal cell-derived factor-1 (SDF-1) plays a vital role in MSC migration and involves activation, mobilization, homing, and retention, which are presumably related to the poor homing in DN therapy. Ultrasound-targeted microbubble destruction has become one of the most promising strategies for the targeted delivery of drugs and genes. To improve MSC homing to DN kidneys, we present a strategy to increase SDF-1 via ultrasound-targeted microbubble destruction. In this study, we developed SDF-1-loaded microbubbles (MB(SDF-1)) via covalent conjugation. The characterization and bioactivity of MB(SDF-1) were assessed in vitro. Target release in the targeted kidneys was triggered with diagnostic ultrasound in combination with MB(SDF-1). The related bioeffects were also elucidated. Early DN was induced in rats with streptozotocin. Green fluorescent protein-labeled MSCs were transplanted intravenously following the target release of SDF-1 in the kidneys of normal and DN rats. The homing efficacy was assessed by detecting the implanted exogenous MSCs at 24 hours. The in vitro results showed an impressive SDF-1 loading efficacy of 79% and a loading content of 15.8 μg/mL. MB(SDF-1) remained bioactive as a chemoattractant. In the in vivo study, SDF-1 was successfully released in the targeted kidneys. The homing efficacy of MSCs to DN kidneys after the target release of SDF-1 was remarkably ameliorated at 24 hours compared with control treatments in normal rats and DN rats. In conclusion, ultrasound-targeted MB(SDF-1) destruction could promote the homing of MSCs to early DN kidneys and provide a novel potential therapeutic approach for DN kidney repair.

Show MeSH
Related in: MedlinePlus