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The Enhanced Permeability and Retention (EPR) effect is a key mechanism for passive tumor targeting, which involves the selective accumulation of therapeutic nanoparticles in tumors due to their unique vascular characteristics. While previous reviews have explored this phenomenon, the present review offers a comprehensive, multidisciplinary approach, highlighting recent advancements in strategies to enhance the EPR effect, as well as novel insights into the role of tumor microenvironment heterogeneity and the multifaceted approaches to overcome EPR-related challenges. This review provides a detailed analysis of the latest developments in nanocarriers’ design, including size, shape, and surface modifications, as well as cutting-edge multi-stage drug delivery systems. Furthermore, the integration of physical, pharmacological, and combinatory therapies to optimize the EPR effect is also discussed, aiming to improve the clinical translation of nanomedicines. Unlike other reviews, this work emphasizes the dynamic interaction between the tumor microenvironment and the vascular network, which remains underexplored in the current literature. In addition, specific clinical trials’ outcomes are highlighted and future directions to address existing limitations are proposed, offering a clearer roadmap regarding clinical applications in cancer therapy.

BackgroundHeart failure is characterized by fluid retention the management of which is critical to clinical care. Due to altered capillary Starling forces in heart failure, the interstitial compartment and lymphatic system act as large reservoirs of fluid accumulation, increasing up to 3-4 times to that of the intravascular compartment. Interstitial fluid pressure (IFP) correlates with indicators of impaired cardiac function including reduced cardiac output and increased cardiac filling pressures. IFP may be measured from a preserved fluid pocket following the maturation of a subcutaneous perforated capsule in animals. However, the structural understanding of tissue neovascularization within a perforated capsule and the temporal relationship between cardiopulmonary haemodynamics and IFP are unknown.MethodsSeven Yorkshire White swine (45-50kg) were implanted with subcutaneous perforated capsules (Home Office Project Licence PP1785781). After 3 weeks animals were anaesthetised and continuous monitoring of IFP, LVEDP, CVP and mPAP was established. Esmolol (10mg/ml, 50ml/hr) was used to blunt the sympathetic response and heart failure induced by infusion of 0.9% NaCl (10% body weight/3 hours, i.v.) until a central venous pressure (CVP) of >15mmHg was maintained. Fluid was then removed to euvolemia via ultrafiltration (3 hours) [figure 1]. To characterise the perforated capsule: 1) serial measurements of venous, interstitial, and subcutaneous glucose were made following a venous glucose bolus (0.5g/kg); 2) a silicone-based liquid perfusion-fixation agent was infused into the arterial system to cast the vasculature for MicroCT and microscopy.ResultsHistology and MicroCT showed neovascularisation of the perforated capsule with a central fluid pocket in communication with the systemic vasculature [figure 2A-D]. A venous bolus of glucose results in diffusion of the micro-molecule from the vasculature into the fluid pocket, however, the large molecule Microfil (silicone-based casting dye) does not diffuse, thereby confirming that the new blood vessels function as a capillary barrier between the vascular and interstitial compartment [figure 3]. IFP, as measured from the perforated fluid pocket, was closely associated with LVEDP, mPAP and CVP during the induction of heart failure and ultrafiltration [figure 4].Abstract BS74 Figure 1Porcine model of acute heart failure. Schematic representation of invasive haemodynamic (LVEDP, CVP and PAP) and subcutaneous interstitial pressure monitoring setup, during the development of acute heart failure (Esmolol and 0.9% NaCl) and fluid offloading through ultrafiltration.Abstract BS74 Figure 2Neovascularization of perforated capsule in a porcine model of heart failure (A-D). A: Anatomical position of the perforated capsule in subcutaneous tissue, B: Macroscopic section demonstrating the finger processes of tissue growth into the capsule, C: MicroCT analysis showing the new vascular growth towards the central fluid pocket, D: Histology (Haemoxylin and Eosin staining) section of perforated capsule demonstrating the angiogenesis.Abstract BS74 Figure 3Measurement of venous, subcutaneous, and interstitial fluid pocket glucose (n=3, mean ± SEM). Diffusion of glucose in the perforated fluid pocket (B) tracks glucose in the venous blood and subcutaneous tissue (A) following venous glucose (5% dextrose water bolus (0.5g/kg).Abstract BS74 Figure 4Relationship between invasive haemodynamics and subcutaneous interstitial pressure. (n=20) Validation of subcutaneous interstitial pressure tracks LVEDP, mPAP and CVP during disease stimulation (N=20 perforated capsules in N=6 animals, thoracic location. Mean ± SEM.ConclusionInterstitial fluid pressure is closely related to invasive hemodynamic indicators of congestion and heart failure. A mature perforated capsule forms a neovascular structure with a central fluid pocket. IFP is closely related to LVEDP at rest and during a haemodynamic challenge. The assessment of interstitial fluid pressure may provide a direct measure of fluid status and an indirect measure of haemodynamics facilitating early identification of clinical worsening and optimization of fluid balance.Conflict of Interestnone

No abstract available [PUBLICATION ABSTRACT]

Background To investigate the in vitro and in vivo anti-inflammatory/anti-fibrotic capacity of IFP-MSC manufactured as 3D spheroids. Our hypothesis is that IFP-MSC do not require prior cell priming to acquire a robust immunomodulatory phenotype in vitro in order to efficiently reverse synovitis and IFP fibrosis, and secondarily delay articular cartilage damage in vivo. Methods Human IFP-MSC immunophenotype, tripotentiality, and transcriptional profiles were assessed in 3D settings. Multiplex secretomes were assessed in IFP-MSC spheroids [Crude (non-immunoselected), CD146 + or CD146 − immunoselected cells] and compared with 2D cultures with and without prior inflammatory/fibrotic cell priming. Functionally, IFP-MSC spheroids were assessed for their immunopotency on human PBMC proliferation and their effect on stimulated synoviocytes with inflammation and fibrotic cues. The anti-inflammatory and anti-fibrotic spheroid properties were further evaluated in vivo in a rat model of acute synovitis/fat pad fibrosis. Results Spheroids enhanced IFP-MSC phenotypic, transcriptional, and secretory immunomodulatory profiles compared to 2D cultures. Further, CD146 + IFP-MSC spheroids showed enhanced secretory and transcriptional profiles; however, these attributes were not reflected in a superior capacity to suppress activated PBMC. This suggests that 3D culturing settings are sufficient to induce an enhanced immunomodulatory phenotype in both Crude and CD146-immunoselected IFP-MSC. Crude IFP-MSC spheroids modulated the molecular response of synoviocytes previously exposed to inflammatory cues. Therapeutically, IFP-MSC spheroids retained substance P degradation potential in vivo, while effectively inducing resolution of inflammation/fibrosis of the synovium and fat pad. Furthermore, their presence resulted in arrest of articular cartilage degradation in a rat model of progressive synovitis and fat pad fibrosis. Conclusions 3D spheroids confer IFP-MSC a reproducible and enhanced immunomodulatory effect in vitro and in vivo, circumventing the requirement of non-compliant cell priming or selection before administration and thereby streamlining cell products manufacturing protocols.

No abstract available [PUBLICATION ABSTRACT]