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Transient mild hyperthermia induces E-selectin mediated localization of mesoporous silicon vectors in solid tumors.

Kirui DK, Mai J, Palange AL, Qin G, van de Ven AL, Liu X, Shen H, Ferrari M - PLoS ONE (2014)

Bottom Line: We also determined the optimal time window at which maximal accumulation occur.By flow chamber experiments and Western blotting, we established that a temporal increase in E-selectin expression correlated with enhanced particle accumulation.Such enhancement in accumulation could be leveraged to increase therapeutic efficacy and reduce drug dosing in cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of NanoMedicine, Houston Methodist Research Institute, Houston, Texas, United States of America.

ABSTRACT

Background: Hyperthermia treatment has been explored as a strategy to overcome biological barriers that hinder effective drug delivery in solid tumors. Most studies have used mild hyperthermia treatment (MHT) to target the delivery of thermo-sensitive liposomes carriers. Others have studied its application to permeabilize tumor vessels and improve tumor interstitial transport. However, the role of MHT in altering tumor vessel interfacial and adhesion properties and its relationship to improved delivery has not been established. In the present study, we evaluated effects of MHT treatment on tumor vessel flow dynamics and expression of adhesion molecules and assessed enhancement in particle localization using mesoporous silicon vectors (MSVs). We also determined the optimal time window at which maximal accumulation occur.

Results: In this study, using intravital microscopy analyses, we showed that temporal mild hyperthermia (∼1 W/cm(2)) amplified delivery and accumulation of MSVs in orthotopic breast cancer tumors. The number of discoidal MSVs (1000×400 nm) adhering to tumor vasculature increased 6-fold for SUM159 tumors and 3-fold for MCF-7 breast cancer tumors. By flow chamber experiments and Western blotting, we established that a temporal increase in E-selectin expression correlated with enhanced particle accumulation. Furthermore, MHT treatment was shown to increase tumor perfusion in a time-dependent fashion.

Conclusions: Our findings reveal that well-timed mild hyperthermia treatment can transiently elevate tumor transport and alter vascular adhesion properties and thereby provides a means to enhance tumor localization of non-thermally sensitive particles such as MSVs. Such enhancement in accumulation could be leveraged to increase therapeutic efficacy and reduce drug dosing in cancer therapy.

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Mild hyperthermia treatment enhances MSV accumulation in a time-dependent manner.A) Representative IVM tissue images of SUM159 tumor show higher accumulation in tumors receiving MHT when analyzed 5 h after treatment; B) quantitative analyses time-dependent increase in accumulation with ∼6-fold increase at 5 h and a reduction in enhancement at 24 h post-treatment (3-fold); C) Histological IVM image illustrating increased MSVs in MCF-7 (less vascularized cell line); D) Quantitative analyses showed similar time-dependent increases in MCF-7 which abated at 24 h. At each time-point, MSVs were injected and allowed 1 h to circulate before analyses. Error bar represents replicates of n = 6, with statistical significance denoted by *** p<0.0001; ** p<0.005; ** p<0.01 for SUM159 and ** p<0.0045 and * p<0.02 for MCF-7 line.
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pone-0086489-g003: Mild hyperthermia treatment enhances MSV accumulation in a time-dependent manner.A) Representative IVM tissue images of SUM159 tumor show higher accumulation in tumors receiving MHT when analyzed 5 h after treatment; B) quantitative analyses time-dependent increase in accumulation with ∼6-fold increase at 5 h and a reduction in enhancement at 24 h post-treatment (3-fold); C) Histological IVM image illustrating increased MSVs in MCF-7 (less vascularized cell line); D) Quantitative analyses showed similar time-dependent increases in MCF-7 which abated at 24 h. At each time-point, MSVs were injected and allowed 1 h to circulate before analyses. Error bar represents replicates of n = 6, with statistical significance denoted by *** p<0.0001; ** p<0.005; ** p<0.01 for SUM159 and ** p<0.0045 and * p<0.02 for MCF-7 line.

Mentions: We next evaluated time-dependent MHT effect and MSV accumulation to obtain the optimal time of opportunity at which MHT treatment can effectively be used to enhance tumoritropic localization. For this study, 60-min time-point was chosen to assess the proportion of adherent particles based on previous finding. MSVs accumulation was evaluated after treatment (up to 24 h) versus controls and also compared to findings obtained from dynamic flow (Figure 2). MSV particles were injected at multiple time-points after MHT treatment using separate animals to analyze accumulation at each time-point where mouse-to-mouse variation were minimized by keeping acquisition parameters same. Histological images illustrating increased accumulation of MSVs across two tumor models shown in Figure 3A, C. By visual inspection, majority of MSVs in both models appeared adhered to vascular walls and at a higher rate in tumors receiving MHT treatment. This suggested that MHT treatment affected vascular endothelium binding properties and interactions with MSV particles (Figure 3 A, C). Quantitative analyses showed a slight increase in MSV accumulation at 1 h and maximal particle augmentation (6-fold increase) at 5 h time-point while the MHT effect appeared to diminish at 24 h after treatment. Similar enhancements in particle accumulation were observed for MCF-7 receiving MHT treatment with ∼4-fold increase at the 5 h time-point compared to control group (Figure 3 C, D). At 24 h, the effect was still statistically significant compared to untreated control but abated relative to the effect at 5 h after treatment. While fewer particles flowing into tumor was observed for MCF-7, enhancement of MSV accumulation was still evident at various time-points. At 1 h post-treatment, there was a slight increase in enhancement, maximal augmentation at 5 h time-point, and a reduction in enhancement at 24 h after treatment. The observation of time-dependent particle accumulation, i.e. maximal MSV accumulation at 5 h and abatement at later time-point, illustrated that this strategy creates a transient a window-of-opportunity with which to increase particle delivery. This suggested that a combination of MHT tumor priming could be optimally used to synergize the delivery of chemotherapeutic-loaded particles such as MSVs.


Transient mild hyperthermia induces E-selectin mediated localization of mesoporous silicon vectors in solid tumors.

Kirui DK, Mai J, Palange AL, Qin G, van de Ven AL, Liu X, Shen H, Ferrari M - PLoS ONE (2014)

Mild hyperthermia treatment enhances MSV accumulation in a time-dependent manner.A) Representative IVM tissue images of SUM159 tumor show higher accumulation in tumors receiving MHT when analyzed 5 h after treatment; B) quantitative analyses time-dependent increase in accumulation with ∼6-fold increase at 5 h and a reduction in enhancement at 24 h post-treatment (3-fold); C) Histological IVM image illustrating increased MSVs in MCF-7 (less vascularized cell line); D) Quantitative analyses showed similar time-dependent increases in MCF-7 which abated at 24 h. At each time-point, MSVs were injected and allowed 1 h to circulate before analyses. Error bar represents replicates of n = 6, with statistical significance denoted by *** p<0.0001; ** p<0.005; ** p<0.01 for SUM159 and ** p<0.0045 and * p<0.02 for MCF-7 line.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3928046&req=5

pone-0086489-g003: Mild hyperthermia treatment enhances MSV accumulation in a time-dependent manner.A) Representative IVM tissue images of SUM159 tumor show higher accumulation in tumors receiving MHT when analyzed 5 h after treatment; B) quantitative analyses time-dependent increase in accumulation with ∼6-fold increase at 5 h and a reduction in enhancement at 24 h post-treatment (3-fold); C) Histological IVM image illustrating increased MSVs in MCF-7 (less vascularized cell line); D) Quantitative analyses showed similar time-dependent increases in MCF-7 which abated at 24 h. At each time-point, MSVs were injected and allowed 1 h to circulate before analyses. Error bar represents replicates of n = 6, with statistical significance denoted by *** p<0.0001; ** p<0.005; ** p<0.01 for SUM159 and ** p<0.0045 and * p<0.02 for MCF-7 line.
Mentions: We next evaluated time-dependent MHT effect and MSV accumulation to obtain the optimal time of opportunity at which MHT treatment can effectively be used to enhance tumoritropic localization. For this study, 60-min time-point was chosen to assess the proportion of adherent particles based on previous finding. MSVs accumulation was evaluated after treatment (up to 24 h) versus controls and also compared to findings obtained from dynamic flow (Figure 2). MSV particles were injected at multiple time-points after MHT treatment using separate animals to analyze accumulation at each time-point where mouse-to-mouse variation were minimized by keeping acquisition parameters same. Histological images illustrating increased accumulation of MSVs across two tumor models shown in Figure 3A, C. By visual inspection, majority of MSVs in both models appeared adhered to vascular walls and at a higher rate in tumors receiving MHT treatment. This suggested that MHT treatment affected vascular endothelium binding properties and interactions with MSV particles (Figure 3 A, C). Quantitative analyses showed a slight increase in MSV accumulation at 1 h and maximal particle augmentation (6-fold increase) at 5 h time-point while the MHT effect appeared to diminish at 24 h after treatment. Similar enhancements in particle accumulation were observed for MCF-7 receiving MHT treatment with ∼4-fold increase at the 5 h time-point compared to control group (Figure 3 C, D). At 24 h, the effect was still statistically significant compared to untreated control but abated relative to the effect at 5 h after treatment. While fewer particles flowing into tumor was observed for MCF-7, enhancement of MSV accumulation was still evident at various time-points. At 1 h post-treatment, there was a slight increase in enhancement, maximal augmentation at 5 h time-point, and a reduction in enhancement at 24 h after treatment. The observation of time-dependent particle accumulation, i.e. maximal MSV accumulation at 5 h and abatement at later time-point, illustrated that this strategy creates a transient a window-of-opportunity with which to increase particle delivery. This suggested that a combination of MHT tumor priming could be optimally used to synergize the delivery of chemotherapeutic-loaded particles such as MSVs.

Bottom Line: We also determined the optimal time window at which maximal accumulation occur.By flow chamber experiments and Western blotting, we established that a temporal increase in E-selectin expression correlated with enhanced particle accumulation.Such enhancement in accumulation could be leveraged to increase therapeutic efficacy and reduce drug dosing in cancer therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of NanoMedicine, Houston Methodist Research Institute, Houston, Texas, United States of America.

ABSTRACT

Background: Hyperthermia treatment has been explored as a strategy to overcome biological barriers that hinder effective drug delivery in solid tumors. Most studies have used mild hyperthermia treatment (MHT) to target the delivery of thermo-sensitive liposomes carriers. Others have studied its application to permeabilize tumor vessels and improve tumor interstitial transport. However, the role of MHT in altering tumor vessel interfacial and adhesion properties and its relationship to improved delivery has not been established. In the present study, we evaluated effects of MHT treatment on tumor vessel flow dynamics and expression of adhesion molecules and assessed enhancement in particle localization using mesoporous silicon vectors (MSVs). We also determined the optimal time window at which maximal accumulation occur.

Results: In this study, using intravital microscopy analyses, we showed that temporal mild hyperthermia (∼1 W/cm(2)) amplified delivery and accumulation of MSVs in orthotopic breast cancer tumors. The number of discoidal MSVs (1000×400 nm) adhering to tumor vasculature increased 6-fold for SUM159 tumors and 3-fold for MCF-7 breast cancer tumors. By flow chamber experiments and Western blotting, we established that a temporal increase in E-selectin expression correlated with enhanced particle accumulation. Furthermore, MHT treatment was shown to increase tumor perfusion in a time-dependent fashion.

Conclusions: Our findings reveal that well-timed mild hyperthermia treatment can transiently elevate tumor transport and alter vascular adhesion properties and thereby provides a means to enhance tumor localization of non-thermally sensitive particles such as MSVs. Such enhancement in accumulation could be leveraged to increase therapeutic efficacy and reduce drug dosing in cancer therapy.

Show MeSH
Related in: MedlinePlus