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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 particle inflow and localization in breast tumor models.A) SEM micrograph of porous MSVs (1000×400 nm) that allow therapeutic loading; B, C) Time-lapse quantification analyses of fluorescently-labeled MSVs in tumor vasculature showing increased initial and total number MSVs in tumors receiving MHT treatment versus control groups. 5-fold enhancement was observed in SUM159 and 3-fold for MCF7; D) Representative time-lapse images from videos acquired over 60 min, showed decreased number of MSVs with time and adherent particles shown after 60 min. Curves represent number of particles monitored in animals (n = 6) injected with 5×108 particles (1000×400 nm, 50 µL PBS) and monitored over 60 min. Error bars represent standard deviation from (n = 6) collected over 8 FOVs per animal. Statistical significance between treatment and control group was determined based 55–60 min time-points after injection where *** show p<0.006 and ** show p<0.02.
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pone-0086489-g002: Mild hyperthermia treatment enhances particle inflow and localization in breast tumor models.A) SEM micrograph of porous MSVs (1000×400 nm) that allow therapeutic loading; B, C) Time-lapse quantification analyses of fluorescently-labeled MSVs in tumor vasculature showing increased initial and total number MSVs in tumors receiving MHT treatment versus control groups. 5-fold enhancement was observed in SUM159 and 3-fold for MCF7; D) Representative time-lapse images from videos acquired over 60 min, showed decreased number of MSVs with time and adherent particles shown after 60 min. Curves represent number of particles monitored in animals (n = 6) injected with 5×108 particles (1000×400 nm, 50 µL PBS) and monitored over 60 min. Error bars represent standard deviation from (n = 6) collected over 8 FOVs per animal. Statistical significance between treatment and control group was determined based 55–60 min time-points after injection where *** show p<0.006 and ** show p<0.02.

Mentions: Transient effects of mild hyperthermia and its potential uses to augment particle accumulation were evaluated by measuring the accumulation of MSVs. These particles, shown in Figure 2 A, are biodegradable drug carriers that have been packaged with a multitude of therapeutic agents [44] and are envisioned as drug depots that lodge onto tumor vasculature [45]. IVM was used to assess the effect of MHT treatment on MSVs accumulation in tumor microenvironment. Initially, we evaluated the effect at a single time-point. MSV accumulation was monitored in real-time for 60 min after injection where tumor-receiving MHT treatment showed more than 2-fold increase in the initial number of particle flowing into tumor compared to SUM159 control group (Figure 2 B). MSV clearance from bloodstream is rapid [28], [36], resulting in time-dependent decrease in the number of circulating particles. Thus, increased particle flow suggested that MHT treatment altered tumor flow dynamics. The total number of particles remaining in tumor microenvironment at 60 min post-injection remained unchanged for both treated and control groups, and thus elected this time-point to evaluate the proportion of MSVs adherent to tumor vasculature. At this point, most of the circulating MSVs had been cleared (Video S2).


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 particle inflow and localization in breast tumor models.A) SEM micrograph of porous MSVs (1000×400 nm) that allow therapeutic loading; B, C) Time-lapse quantification analyses of fluorescently-labeled MSVs in tumor vasculature showing increased initial and total number MSVs in tumors receiving MHT treatment versus control groups. 5-fold enhancement was observed in SUM159 and 3-fold for MCF7; D) Representative time-lapse images from videos acquired over 60 min, showed decreased number of MSVs with time and adherent particles shown after 60 min. Curves represent number of particles monitored in animals (n = 6) injected with 5×108 particles (1000×400 nm, 50 µL PBS) and monitored over 60 min. Error bars represent standard deviation from (n = 6) collected over 8 FOVs per animal. Statistical significance between treatment and control group was determined based 55–60 min time-points after injection where *** show p<0.006 and ** show p<0.02.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0086489-g002: Mild hyperthermia treatment enhances particle inflow and localization in breast tumor models.A) SEM micrograph of porous MSVs (1000×400 nm) that allow therapeutic loading; B, C) Time-lapse quantification analyses of fluorescently-labeled MSVs in tumor vasculature showing increased initial and total number MSVs in tumors receiving MHT treatment versus control groups. 5-fold enhancement was observed in SUM159 and 3-fold for MCF7; D) Representative time-lapse images from videos acquired over 60 min, showed decreased number of MSVs with time and adherent particles shown after 60 min. Curves represent number of particles monitored in animals (n = 6) injected with 5×108 particles (1000×400 nm, 50 µL PBS) and monitored over 60 min. Error bars represent standard deviation from (n = 6) collected over 8 FOVs per animal. Statistical significance between treatment and control group was determined based 55–60 min time-points after injection where *** show p<0.006 and ** show p<0.02.
Mentions: Transient effects of mild hyperthermia and its potential uses to augment particle accumulation were evaluated by measuring the accumulation of MSVs. These particles, shown in Figure 2 A, are biodegradable drug carriers that have been packaged with a multitude of therapeutic agents [44] and are envisioned as drug depots that lodge onto tumor vasculature [45]. IVM was used to assess the effect of MHT treatment on MSVs accumulation in tumor microenvironment. Initially, we evaluated the effect at a single time-point. MSV accumulation was monitored in real-time for 60 min after injection where tumor-receiving MHT treatment showed more than 2-fold increase in the initial number of particle flowing into tumor compared to SUM159 control group (Figure 2 B). MSV clearance from bloodstream is rapid [28], [36], resulting in time-dependent decrease in the number of circulating particles. Thus, increased particle flow suggested that MHT treatment altered tumor flow dynamics. The total number of particles remaining in tumor microenvironment at 60 min post-injection remained unchanged for both treated and control groups, and thus elected this time-point to evaluate the proportion of MSVs adherent to tumor vasculature. At this point, most of the circulating MSVs had been cleared (Video S2).

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