Nanocarriers offer a promising approach to significantly improve therapeutic delivery to solid tumors as well as limit the side effects associated with anti-cancer agents. However, their relatively large size can negatively affect their ability to efficiently penetrate into more interior tumor regions, ultimately reducing therapeutic efficacy. Poor penetration of large agents such as nanocarriers is attributed to factors in the tumor microenvironment such as elevated interstitial fluid pressure (IFP) and fibrillar collagen in the extracellular matrix. Our previous studies reported that pretreatment of solid tumor xenografts with nondestructive pulsed focused ultrasound (pFUS) can improve the delivery and subsequent therapy of a variety of therapeutic formulations in different tumor models, where the results were associated with expanded extracellular spaces (ECS), an increase in hydraulic conductivity, and decrease in tissue stiffness. Here, we demonstrate the inverse relationship between IFP and the penetration of systemically administered nanoparticle (NP) probes, where IFP increased from the tumor periphery to their center. Furthermore, we show that pretreatment with pFUS can safely reduce IFP and improve NP delivery; especially into the center of the tumors. These results coincide with effects generated in the fibrillar collagen network microstructure in the ECS as determined by quantitative polarized light microscopy. Whole tumor and histomorphometric analysis, however, did not show significant differences in collagen area fraction or collagen feature solidity, as well as tumor cross-sectional area and aspect ratio, as a result of the treatments. We present a biophysical model connecting the experimental results, where pFUS-mediated cytoarchitectural changes are associated with improved redistribution of the interstitial fluid and lower IFP. The resulting improvement in NP delivery supports our previous therapeutic studies and may have implications for clinical applications to improve therapeutic outcomes in cancer therapy.
Introduction. DFUs remain a cause of significant morbidity. Objective. This is the third of 3 planned articles reporting on a prospective, multicenter, randomized controlled trial evaluating the use of omega-3–rich acellular FSG compared with CAT in the management of DFUs. Materials and Methods. A total of 102 patients with a DFU (n = 51 FSG, n = 51 CAT) participated in the trial as ITT candidates, with 77 of those patients included in the PP analysis (n = 43 FSG, n = 34 CAT). Six months after treatment, patients with healed ulcers were followed up for ulcer recurrence. A cost analysis model was applied in both treatment groups. Results. The proportion of closed wounds at 12 weeks was compared, as were the secondary outcomes of healing rate and mean PAR. Diabetic foot wounds treated with FSG were significantly more likely to achieve closure than those managed with CAT (ITT: 56.9% vs 31.4%; P =.0163). The mean PAR at 12 weeks was 86.3% for FSG vs 64.0% for CAT (P =.0282). Conclusions. Treatment of DFUs with FSG resulted in significantly more wounds healed and an annualized cost savings of $2818 compared with CAT.
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