Ultrasound and microbubbles to beat barriers in tumors: Improving delivery of nanomedicine

Successful delivery of drugs and nanomedicine to tumors requires a functional vascular network, extravasation across the capillary wall, penetration through the extracellular matrix, and cellular uptake. Nanomedicine has many merits, but penetration deep into the tumor interstitium remains a challenge. Failure of cancer treatment can be caused by insufficient delivery of the therapeutic agents. After intra-venous administration, nanomedicines are often found in off-target organs and the tumor extracellular matrix close to the capillary wall. With circulating microbubbles, ultrasound exposure focused toward the tumor shows great promise in improving the delivery of therapeutic agents. In this review, we address the impact of focused ultrasound and microbubbles to overcome barriers for drug delivery such as perfusion, extravasation, and transport through the extracellular matrix. Furthermore, we discuss the induction of an immune response with ultrasound and delivery of immuno-therapeutics. The review dis-cusses mainly preclinical results and ends with a summary of ongoing clinical trials.publishedVersio

Ultrasound and microbubbles to beat barriers in tumors: Improving delivery of nanomedicine

Successful delivery of drugs and nanomedicine to tumors requires a functional vascular network, extravasation across the capillary wall, penetration through the extracellular matrix, and cellular uptake. Nanomedicine has many merits, but penetration deep into the tumor interstitium remains a challenge. Failure of cancer treatment can be caused by insufficient delivery of the therapeutic agents. After intra-venous administration, nanomedicines are often found in off-target organs and the tumor extracellular matrix close to the capillary wall. With circulating microbubbles, ultrasound exposure focused toward the tumor shows great promise in improving the delivery of therapeutic agents. In this review, we address the impact of focused ultrasound and microbubbles to overcome barriers for drug delivery such as perfusion, extravasation, and transport through the extracellular matrix. Furthermore, we discuss the induction of an immune response with ultrasound and delivery of immuno-therapeutics. The review dis-cusses mainly preclinical results and ends with a summary of ongoing clinical trials

Ultrasound and microbubbles to beat barriers in tumors: Improving delivery of nanomedicine

Successful delivery of drugs and nanomedicine to tumors requires a functional vascular network, extravasation across the capillary wall, penetration through the extracellular matrix, and cellular uptake. Nanomedicine has many merits, but penetration deep into the tumor interstitium remains a challenge. Failure of cancer treatment can be caused by insufficient delivery of the therapeutic agents. After intra-venous administration, nanomedicines are often found in off-target organs and the tumor extracellular matrix close to the capillary wall. With circulating microbubbles, ultrasound exposure focused toward the tumor shows great promise in improving the delivery of therapeutic agents. In this review, we address the impact of focused ultrasound and microbubbles to overcome barriers for drug delivery suchnas perfusion, extravasation, and transport through the extracellular matrix. Furthermore, we discuss the induction of an immune response with ultrasound and delivery of immuno-therapeutics. The review dis-cusses mainly preclinical results and ends with a summary of ongoing clinical trials

Sonopermeation with nanoparticle-stabilized microbubbles reduces solid stress and improves nanomedicine delivery to tumors

Drug delivery to tumors is challenging due to biological barriers obstructing effective delivery. Sonopermeation with ultrasound and microbubbles has been shown to improve therapeutic effect of many classes of drugs, but the underlying mechanism is not fully understood. In this study, two subcutaneous xenograft tumor models, that differed substantially in blood vessel density and stiffness, is treated with poly(alkyl cyanoacrylate) nanoparticles and nanoparticle-stabilized microbubbles combined with ultrasound. Improved nanoparticle accumulation and extracellular matrix (ECM) penetration is found. The stiffness and solid stress in the tumors are measured and it is discovered that sonopermeation can reduce the solid stress in both models, with the highest effect in the stiffest tumor model. This suggests that sonopermeation affects not only the blood vessel wall which has been described previously, but also the ECM to reduce solid stress and increase diffusion and transport of nanomedicines.publishedVersio

Sonopermeation with nanoparticle-stabilized microbubbles reduces solid stress and improves nanomedicine delivery to tumors

Drug delivery to tumors is challenging due to biological barriers obstructing effective delivery. Sonopermeation with ultrasound and microbubbles has been shown to improve therapeutic effect of many classes of drugs, but the underlying mechanism is not fully understood. In this study, two subcutaneous xenograft tumor models, that differed substantially in blood vessel density and stiffness, is treated with poly(alkyl cyanoacrylate) nanoparticles and nanoparticle-stabilized microbubbles combined with ultrasound. Improved nanoparticle accumulation and extracellular matrix (ECM) penetration is found. The stiffness and solid stress in the tumors are measured and it is discovered that sonopermeation can reduce the solid stress in both models, with the highest effect in the stiffest tumor model. This suggests that sonopermeation affects not only the blood vessel wall which has been described previously, but also the ECM to reduce solid stress and increase diffusion and transport of nanomedicines

Sonopermeation with nanoparticle-stabilized microbubbles reduces solid stress and improves nanomedicine delivery to tumors

Drug delivery to tumors is challenging due to biological barriers obstructing effective delivery. Sonopermeation with ultrasound and microbubbles has been shown to improve therapeutic effect of many classes of drugs, but the underlying mechanism is not fully understood. In this study, two subcutaneous xenograft tumor models, that differed substantially in blood vessel density and stiffness, is treated with poly(alkyl cyanoacrylate) nanoparticles and nanoparticle-stabilized microbubbles combined with ultrasound. Improved nanoparticle accumulation and extracellular matrix (ECM) penetration is found. The stiffness and solid stress in the tumors are measured and it is discovered that sonopermeation can reduce the solid stress in both models, with the highest effect in the stiffest tumor model. This suggests that sonopermeation affects not only the blood vessel wall which has been described previously, but also the ECM to reduce solid stress and increase diffusion and transport of nanomedicines

A Comparative Analysis of Orthotopic and Subcutaneous Pancreatic Tumour Models: Tumour Microenvironment and Drug Delivery

Pancreatic ductal adenocarcinoma (PDAC) remains a challenging malignancy, mainly due to its resistance to chemotherapy and its complex tumour microenvironment characterised by stromal desmoplasia. There is a need for new strategies to improve the delivery of drugs and therapeutic response. Relevant preclinical tumour models are needed to test potential treatments. This paper compared orthotopic and subcutaneous PDAC tumour models and their suitability for drug delivery studies. A novel aspect was the broad range of tumour properties that were studied, including tumour growth, histopathology, functional vasculature, perfusion, immune cell infiltration, biomechanical characteristics, and especially the extensive analysis of the structure and the orientation of the collagen fibres in the two tumour models. The study unveiled new insights into how these factors impact the uptake of a fluorescent model drug, the macromolecule called 800CW. While the orthotopic model offered a more clinically relevant microenvironment, the subcutaneous model offered advantages for drug delivery studies, primarily due to its reproducibility, and it was characterised by a more efficient drug uptake facilitated by its collagen organisation and well-perfused vasculature. The tumour uptake seemed to be influenced mainly by the structural organisation and the alignment of the collagen fibres and perfusion. Recognising the diverse characteristics of these models and their multifaceted impacts on drug delivery is crucial for designing clinically relevant experiments and improving our understanding of pancreatic cancer biology