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Theranostic mesoporous silica nanoparticles biodegrade after pro-survival drug delivery and ultrasound/magnetic resonance imaging of stem cells.

Kempen PJ, Greasley S, Parker KA, Campbell JL, Chang HY, Jones JR, Sinclair R, Gambhir SS, Jokerst JV - Theranostics (2015)

Bottom Line: Second, the nanoparticle serves as a slow release reservoir of insulin-like growth factor (IGF)-a protein shown to increase cell survival.We also studied the degradation of the nanoparticles and showed that they clear from cells in approximately 3 weeks.The presence of IGF increased cell survival up to 40% (p<0.05) versus unlabeled cells under in vitro serum-free culture conditions.

View Article: PubMed Central - PubMed

Affiliation: 1. Molecular Imaging Program at Stanford (MIPS), Department of Radiology, 318 Campus Drive, Stanford University School of Medicine, Stanford, CA 94305-5427; ; 2. Materials Science & Engineering, Stanford University, Stanford, CA 94305;

ABSTRACT
Increasing cell survival in stem cell therapy is an important challenge for the field of regenerative medicine. Here, we report theranostic mesoporous silica nanoparticles that can increase cell survival through both diagnostic and therapeutic approaches. First, the nanoparticle offers ultrasound and MRI signal to guide implantation into the peri-infarct zone and away from the most necrotic tissue. Second, the nanoparticle serves as a slow release reservoir of insulin-like growth factor (IGF)-a protein shown to increase cell survival. Mesenchymal stem cells labeled with these nanoparticles had detection limits near 9000 cells with no cytotoxicity at the 250 µg/mL concentration required for labeling. We also studied the degradation of the nanoparticles and showed that they clear from cells in approximately 3 weeks. The presence of IGF increased cell survival up to 40% (p<0.05) versus unlabeled cells under in vitro serum-free culture conditions.

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Biodegradation of the MSNs. MSCs were labeled with MSNs and cultured for 1 (A), 2 (B), or 3 (C) weeks and then analyzed with TEM. A similar change in morphology is seen as the in vitro experiments including a hollowing from the inside out and finally a collapse (C). The smaller panels (Ai, Bi, and Ci) show digital magnification to highlight the nanoparticle degradation. Arrows indicate smaller fragments of MSNs. During this experiment, media from the adherent cells was collected periodically and measured for Si with ICP (D). The three washes after labeling show decreasing Si content as free MSNs are removed. The concentration peaks at day 2 and then gradually decreases to baseline near day 11. (E) The EDS data of areas with nanoparticles shows decreasing Si and O signal as a function of time. Scale bars in A-C represent 250 nm, and those in Ai-Ci are 125 nm. Error bars in D represent the standard deviation of 3 replicates (up to day 7) and 2 replicates (days 9-14).
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Figure 4: Biodegradation of the MSNs. MSCs were labeled with MSNs and cultured for 1 (A), 2 (B), or 3 (C) weeks and then analyzed with TEM. A similar change in morphology is seen as the in vitro experiments including a hollowing from the inside out and finally a collapse (C). The smaller panels (Ai, Bi, and Ci) show digital magnification to highlight the nanoparticle degradation. Arrows indicate smaller fragments of MSNs. During this experiment, media from the adherent cells was collected periodically and measured for Si with ICP (D). The three washes after labeling show decreasing Si content as free MSNs are removed. The concentration peaks at day 2 and then gradually decreases to baseline near day 11. (E) The EDS data of areas with nanoparticles shows decreasing Si and O signal as a function of time. Scale bars in A-C represent 250 nm, and those in Ai-Ci are 125 nm. Error bars in D represent the standard deviation of 3 replicates (up to day 7) and 2 replicates (days 9-14).

Mentions: These labeled cells were further studied to understand biodegradation inside of cells. MSCs labeled with the MSNs were imaged with TEM 1, 2, and 3 weeks after labeling (Fig. 4). At one week, many MSNs are still present in the cells (Fig. 4A). This was confirmed with EDS data—all 9 of 9 spots imaged had a robust silicon peak (Fig. 4E). However, by 2 weeks, the MSNs had less organized structures (Fig. 4B). By week 3 no MSNs could be seen, except for some extremely collapsed structures (Fig. 4C). Although some spherical objects were noted, EDS analysis indicated only osmium from the staining protocol and thus were not MSNs (only 3 of 9 spots imaged with EDS had Si peaks above background).


Theranostic mesoporous silica nanoparticles biodegrade after pro-survival drug delivery and ultrasound/magnetic resonance imaging of stem cells.

Kempen PJ, Greasley S, Parker KA, Campbell JL, Chang HY, Jones JR, Sinclair R, Gambhir SS, Jokerst JV - Theranostics (2015)

Biodegradation of the MSNs. MSCs were labeled with MSNs and cultured for 1 (A), 2 (B), or 3 (C) weeks and then analyzed with TEM. A similar change in morphology is seen as the in vitro experiments including a hollowing from the inside out and finally a collapse (C). The smaller panels (Ai, Bi, and Ci) show digital magnification to highlight the nanoparticle degradation. Arrows indicate smaller fragments of MSNs. During this experiment, media from the adherent cells was collected periodically and measured for Si with ICP (D). The three washes after labeling show decreasing Si content as free MSNs are removed. The concentration peaks at day 2 and then gradually decreases to baseline near day 11. (E) The EDS data of areas with nanoparticles shows decreasing Si and O signal as a function of time. Scale bars in A-C represent 250 nm, and those in Ai-Ci are 125 nm. Error bars in D represent the standard deviation of 3 replicates (up to day 7) and 2 replicates (days 9-14).
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Related In: Results  -  Collection

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Figure 4: Biodegradation of the MSNs. MSCs were labeled with MSNs and cultured for 1 (A), 2 (B), or 3 (C) weeks and then analyzed with TEM. A similar change in morphology is seen as the in vitro experiments including a hollowing from the inside out and finally a collapse (C). The smaller panels (Ai, Bi, and Ci) show digital magnification to highlight the nanoparticle degradation. Arrows indicate smaller fragments of MSNs. During this experiment, media from the adherent cells was collected periodically and measured for Si with ICP (D). The three washes after labeling show decreasing Si content as free MSNs are removed. The concentration peaks at day 2 and then gradually decreases to baseline near day 11. (E) The EDS data of areas with nanoparticles shows decreasing Si and O signal as a function of time. Scale bars in A-C represent 250 nm, and those in Ai-Ci are 125 nm. Error bars in D represent the standard deviation of 3 replicates (up to day 7) and 2 replicates (days 9-14).
Mentions: These labeled cells were further studied to understand biodegradation inside of cells. MSCs labeled with the MSNs were imaged with TEM 1, 2, and 3 weeks after labeling (Fig. 4). At one week, many MSNs are still present in the cells (Fig. 4A). This was confirmed with EDS data—all 9 of 9 spots imaged had a robust silicon peak (Fig. 4E). However, by 2 weeks, the MSNs had less organized structures (Fig. 4B). By week 3 no MSNs could be seen, except for some extremely collapsed structures (Fig. 4C). Although some spherical objects were noted, EDS analysis indicated only osmium from the staining protocol and thus were not MSNs (only 3 of 9 spots imaged with EDS had Si peaks above background).

Bottom Line: Second, the nanoparticle serves as a slow release reservoir of insulin-like growth factor (IGF)-a protein shown to increase cell survival.We also studied the degradation of the nanoparticles and showed that they clear from cells in approximately 3 weeks.The presence of IGF increased cell survival up to 40% (p<0.05) versus unlabeled cells under in vitro serum-free culture conditions.

View Article: PubMed Central - PubMed

Affiliation: 1. Molecular Imaging Program at Stanford (MIPS), Department of Radiology, 318 Campus Drive, Stanford University School of Medicine, Stanford, CA 94305-5427; ; 2. Materials Science & Engineering, Stanford University, Stanford, CA 94305;

ABSTRACT
Increasing cell survival in stem cell therapy is an important challenge for the field of regenerative medicine. Here, we report theranostic mesoporous silica nanoparticles that can increase cell survival through both diagnostic and therapeutic approaches. First, the nanoparticle offers ultrasound and MRI signal to guide implantation into the peri-infarct zone and away from the most necrotic tissue. Second, the nanoparticle serves as a slow release reservoir of insulin-like growth factor (IGF)-a protein shown to increase cell survival. Mesenchymal stem cells labeled with these nanoparticles had detection limits near 9000 cells with no cytotoxicity at the 250 µg/mL concentration required for labeling. We also studied the degradation of the nanoparticles and showed that they clear from cells in approximately 3 weeks. The presence of IGF increased cell survival up to 40% (p<0.05) versus unlabeled cells under in vitro serum-free culture conditions.

Show MeSH
Related in: MedlinePlus