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The tumor develops defense tactics, including conversing the mechanical characteristics of tumor cells and their surrounding environment. A recent study reported that cholesterol depletion stiffens tumor cells, which could enhance adaptive T-cell immunotherapy. However, it remains unclear whether reducing the cholesterol in tumor cells contributes to re-educating the stiff tumor matrix, which serves as a physical barrier against drug penetration. Herein, we found that depleting cholesterol from tumor cells can demolish the intratumor physical barrier by disrupting the mechanical signal transduction between tumor cells and the extracellular matrix through the destruction of lipid rafts. This disruption allows nanoparticles (H/S@hNP) to penetrate deeply, resulting in improved photodynamic treatment. Our research also indicates that cholesterol depletion can inhibit the epithelial-mesenchymal transition and repolarize tumor-associated macrophages from M2 to M1, demonstrating the essential role of cholesterol in tumor progression. Overall, this study reveals that a cholesterol-depleted, softened tumor matrix reduces the difficulty of drug penetration, leading to enhanced antitumor therapeutics. [Display omitted] • H/S@hNP could soften the stiff tumor matrix via cholesterol-depletion strategy. • H/S@hNP mediated cholesterol depletion enhanced nanoparticle penetration and photodynamic therapy antitumor efficacy. • H/S@hNP could hamper epithelial-mesenchymal transition and switch tumor-associated macrophages from M2 to M1. [ABSTRACT FROM AUTHOR]

Organ-on-a-chip technologies show exponential growth driven by the need to reduce the number of experimental animals and develop physiologically relevant human models for testing drugs. In vitro, microfluidic devices should be carefully designed and fabricated to provide reliable tools for modeling physiological or pathological conditions and assessing, for example, drug delivery through biological barriers. The aim of the current study was to optimize the utilization of three existing skin-on-a-chip microfluidic diffusion chambers with various designs. For this, different perfusion flow rates were compared using cellulose acetate membrane, polyester membrane, excised rat skin, and acellular alginate scaffold in the chips. These diffusion platforms were integrated into a single-channel microfluidic diffusion chamber, a multi-channel chamber, and the LiveBox2 system. The experimental results revealed that the 40 µL/min flow rate resulted in the highest diffusion of the hydrophilic model formulation (2% caffeine cream) in each system. The single-channel setup was used for further analysis by computational fluid dynamics simulation. The visualization of shear stress and fluid velocity within the microchannel and the presentation of caffeine progression with the perfusion fluid were consistent with the measured data. These findings contribute to the development and effective application of microfluidic systems for penetration testing. [ABSTRACT FROM AUTHOR]

Aim: To establish a methodology for understanding how ultrasound (US) induces drug release from nano-sized drug-delivery systems (NSDDSs) and enhances drug penetration and uptake in tumors. This aims to advance cancer treatment strategies. Materials & methods: We developed a multi-physics mathematical model to elucidate and understand the intricate mechanisms governing drug release, transport and delivery. Unique in vitro models (monolayer, multilayer, spheroid) and a tailored US exposure setup were introduced to evaluate drug penetration and uptake. Results: The results highlight the potential advantages of US-mediated NSDDSs over conventional NSDDSs and chemotherapy, notably in enhancing drug release and inducing cell death. Conclusion: Our sophisticated numerical and experimental methods aid in determining and quantifying drug penetration and uptake into solid tumors. Therapeutic ultrasound (TUS) permits targeted drug delivery by controlling the drug-release kinetics, thereby enhancing drug delivery and cell killing in tumors. Our study enabled a comprehensive understanding of the integration of TUS and nano-sized drug-delivery systems by combining experimental and theoretical analyses. We introduced a multi-scale and multi-physics mathematical and computational model for the penetration of TUS-triggered nano-sized drug-delivery systems into solid tumors. We examined three in vitro cancer cell culture methods – 2D monolayer, 3D spheroids and 3D multi-layer cells – to analyze initial cell toxicity, antiproliferative capacity and drug penetration. A customized experimental setup was developed that was suitable for TUS (i.e., LIPUS) and cell studies. The synergies between TUS, drug-release kinetics and transport characteristics were explored to increase the rate of cancer cell death. We proposed an optical sectioning technique for drug-penetration studies and utilized flow cytometry analysis for cell proliferation studies in a spheroid cancer cell model. Drug-release kinetics were determined with and without ultrasound exposure at 37°C. [ABSTRACT FROM AUTHOR]

Misfolding and aggregation of specific proteins are associated with liquid-liquid phase separation (LLPS), and these protein aggregates can interfere with normal cellular functions and even lead to cell death, possibly affecting gene expression regulation and cell proliferation. Therefore, understanding the role of LLPS in disease may help to identify new mechanisms or therapeutic targets and provide new strategies for disease treatment. There are several ways to disrupt LLPS, including screening small molecules or small molecule drugs to target the upstream signaling pathways that regulate the LLPS process, selectively dissolve and destroy RNA droplets or protein aggregates, regulate the conformation of mutant protein, activate the protein degradation pathway to remove harmful protein aggregates. Furthermore, harnessing the mechanism of LLPS can improve drug development, including preparing different kinds of drug delivery carriers (microneedles, nanodrugs, imprints), regulating drug internalization and penetration behaviors, screening more drugs to overcome drug resistance and enhance receptor signaling. This review initially explores the correlation between aberrant LLPS and disease, highlighting the pivotal role of LLPS in preparing drug development. Ultimately, a comprehensive investigation into drug-mediated regulation of LLPS processes holds significant scientific promise for disease management.

Abstract Background Vasculogenic mimicry (VM), when microvascular channels are formed by cancer cells independent of endothelial cells, often occurs in deep hypoxic areas of tumors and contributes to the aggressiveness and metastasis of triple-negative breast cancer (TNBC) cells. However, well-developed VM inhibitors exhibit inadequate efficacy due to their low drug utilization rate and limited deep penetration. Thus, a cost-effective VM inhibition strategy needs to be designed for TNBC treatment. Results Herein, we designed a low-intensity focused ultrasound (LIFU) and matrix metalloproteinase-2 (MMP-2) dual-responsive nanoplatform termed PFP@PDM-PEG for the cost-effective and efficient utilization of the drug disulfiram (DSF) as a VM inhibitor. The PFP@PDM-PEG nanodroplets effectively penetrated tumors and exhibited substantial accumulation facilitated by PEG deshielding in a LIFU-mediated and MMP-2-sensitive manner. Furthermore, upon exposure to LIFU irradiation, DSF was released controllably under ultrasound imaging guidance. This secure and controllable dual-response DSF delivery platform reduced VM formation by inhibiting COL1/pro-MMP-2 activity, thereby significantly inhibiting tumor progression and metastasis. Conclusions Considering the safety of the raw materials, controlled treatment process, and reliable repurposing of DSF, this dual-responsive nanoplatform represents a novel and effective VM-based therapeutic strategy for TNBC in clinical settings. Graphical Abstract

Background: Vasculogenic mimicry (VM), when microvascular channels are formed by cancer cells independent of endothelial cells, often occurs in deep hypoxic areas of tumors and contributes to the aggressiveness and metastasis of triple-negative breast cancer (TNBC) cells. However, well-developed VM inhibitors exhibit inadequate efficacy due to their low drug utilization rate and limited deep penetration. Thus, a cost-effective VM inhibition strategy needs to be designed for TNBC treatment. Results: Herein, we designed a low-intensity focused ultrasound (LIFU) and matrix metalloproteinase-2 (MMP-2) dual-responsive nanoplatform termed PFP@PDM-PEG for the cost-effective and efficient utilization of the drug disulfiram (DSF) as a VM inhibitor. The PFP@PDM-PEG nanodroplets effectively penetrated tumors and exhibited substantial accumulation facilitated by PEG deshielding in a LIFU-mediated and MMP-2-sensitive manner. Furthermore, upon exposure to LIFU irradiation, DSF was released controllably under ultrasound imaging guidance. This secure and controllable dual-response DSF delivery platform reduced VM formation by inhibiting COL1/pro-MMP-2 activity, thereby significantly inhibiting tumor progression and metastasis. Conclusions: Considering the safety of the raw materials, controlled treatment process, and reliable repurposing of DSF, this dual-responsive nanoplatform represents a novel and effective VM-based therapeutic strategy for TNBC in clinical settings. [ABSTRACT FROM AUTHOR]

AbstractThe transungual drug delivery system refers to the administration of drugs through the nail plate to treat various nail disorders such as fungal infections, psoriasis, and nail dystrophies. The nail plate is a challenging barrier for drug penetration due to its highly keratinized and tightly packed structure, which limits the permeation of topically applied drugs. Owing to several problems associated with oral therapy, topical therapy remains a preferred treatment option for nail infections due to less side effects, and cost-effectiveness. On the other hand, the drugs that have low permeability across the nail plate highlight the need for further research in this area. Researchers working on various aspects to increase drug penetration across the nail plate, which include the use of chemical penetration enhancers, mechanical methods, and physical methods. Recent advances in transungual drug delivery systems have led to the development of antifungal nail lacquers that can penetrate the nail plate and effectively treat nail infections. Other transungual drug delivery systems under investigation include microneedles, ultrasound, and laser-assisted treatment, which can create micropores in the nail plate allowing higher drug delivery. This indicates the potential of research on transungual drug delivery systems. By understanding the anatomy of the nail, utilizing appropriate penetration-enhancing methods, and selecting appropriate drug formulations, the effectiveness of the system can be developed and utilized. [ABSTRACT FROM AUTHOR]

Organ-on-a-chip technologies show exponential growth driven by the need to reduce the number of experimental animals and develop physiologically relevant human models for testing drugs. In vitro, microfluidic devices should be carefully designed and fabricated to provide reliable tools for modeling physiological or pathological conditions and assessing, for example, drug delivery through biological barriers. The aim of the current study was to optimize the utilization of three existing skin-on-a-chip microfluidic diffusion chambers with various designs. For this, different perfusion flow rates were compared using cellulose acetate membrane, polyester membrane, excised rat skin, and acellular alginate scaffold in the chips. These diffusion platforms were integrated into a single-channel microfluidic diffusion chamber, a multi-channel chamber, and the LiveBox2 system. The experimental results revealed that the 40 µL/min flow rate resulted in the highest diffusion of the hydrophilic model formulation (2% caffeine cream) in each system. The single-channel setup was used for further analysis by computational fluid dynamics simulation. The visualization of shear stress and fluid velocity within the microchannel and the presentation of caffeine progression with the perfusion fluid were consistent with the measured data. These findings contribute to the development and effective application of microfluidic systems for penetration testing.

Animal models are still used in the research and development of ophthalmic drug products, mainly due to the difficulty in simulating natural physiological conditions with in vitro models, as there is a lack of dynamic protection mechanisms. Therefore, developing alternative ophthalmic models that evaluate drug penetration in the cornea while applying dynamic protection barriers is a contemporary challenge. This study aimed to develop a dynamic ex vivo model using porcine eyes with a simulated lacrimal flow to evaluate the performance of pharmaceutical drug products. A glass donor cell to support a simulated tear flow was designed, optimized, and custom-made. The system was challenged with different formulations (with fluconazole) including excipients with different viscosities (poloxamer 407) and mucoadhesive properties (chitosan). The results were compared to those obtained from a conventional excised cornea model mounted in Franz-type diffusion cells. The dynamic model could differentiate formulations, while the static model did not, overestimating ex vivo drug penetrated amounts. Hence, the dynamic model with simulated tear flow showed to be a simple and promising new alternative method for the drug penetration of ophthalmic formulations that ultimately can reduce the number of animals used in research. [ABSTRACT FROM AUTHOR]

The essential oil, extracted from the Hmong medicine Blumea balsamifera (L.) DC. (BBO), is a purely natural wound repair agent. Its application has, however, been restricted due to its low solubility and high volatility properties. In this study, we have developed a nanoemulsion formulation to improve the characteristics of BBO. The particle size of the nanoemulsion was normally distributed, and 71% of its range was concentrated between 10-100 nm, with an average particle size of 62.8 nm and an encapsulation rate of 98%. After 7 days of application, the wound healing rate of the BBO nanoemulsion (BBO-NE) group was 1.5 times higher than that of the normal BBO group. Along with histological observations, nanoemulsion formulation has been demonstrated to significantly improve the efficacy of BBO for wound repair. In addition, inflammation-related TLR4, CD14 and IRAK-1 gene transcript levels were significantly reduced after the administration of BBO-NE compared to the BBO group, with downregulation of 47.8%, 35.7% and 57.8%, respectively, while the secretion of pro-inflammatory factors IL-6 and TNF-a was also significantly reduced by 83.8% and 32.7%, respectively, in the nanoformulation administration (BBO-NE) group compared to the BBO group. In contrast, the anti-inflammatory factor IL-10 was significantly increased by 4.2-fold. It was further found that the drug penetration per unit area increased significantly 6.30% to 19.5% at different time points after the application of the BBO-NE compared to the BBO. In conclusion, nano-formulation enhanced the drug penetration of the BBO, reduced inflammatory factors, increased the level of anti-inflammatory factors, and promoted collagen deposition, thereby accelerating wound repair. [ABSTRACT FROM AUTHOR]

Studies of the choroid plexus lag behind those of the more widely known blood-brain barrier, despite a much longer history. This review has two overall aims. The first is to outline long-standing areas of research where there are unanswered questions, such as control of cerebrospinal fluid (CSF) secretion and blood flow. The second aim is to review research over the past 10 years where the focus has shifted to the idea that there are choroid plexuses located in each of the brain's ventricles that make specific contributions to brain development and function through molecules they generate for delivery via the CSF. These factors appear to be particularly important for aspects of normal brain growth. Most research carried out during the twentieth century dealt with the choroid plexus, a brain barrier interface making critical contributions to the composition and stability of the brain's internal environment throughout life. More recent research in the twenty-first century has shown the importance of choroid plexus-generated CSF in neurogenesis, influence of sex and other hormones on choroid plexus function, and choroid plexus involvement in circadian rhythms and sleep. The advancement of technologies to facilitate delivery of brain-specific therapies via the CSF to treat neurological disorders is a rapidly growing area of research. Conversely, understanding the basic mechanisms and implications of how maternal drug exposure during pregnancy impacts the developing brain represents another key area of research. [ABSTRACT FROM AUTHOR]

[Display omitted] • Thrombotic microenvironment—NIR laser dual responsive drug release. • Locally transformed heat-gas dual propulsion nanomotor promoted deep penetration of UK in the thrombus. • Photothermal assisted thrombolysis. • The released NO in situ could prevent re-embolism of blood vessels at the thrombolytic site. • Effectively reducing uncontrolled bleeding risk of thrombolytic drug. Drug thrombolysis is the main means of clinical treatment for thrombotic-related diseases. However, serious bleeding complications caused by low drug delivery efficiency and secondary vascular embolism usually lead to unsatisfactory therapeutic effects. Herein, we constructed a thrombin and near-infrared (NIR) dual-responsive drug-loaded intelligent system to solve the above problems. The CREKA-modified polydopamine (PDA) nanoparticles (NPs) were crosslinked by thrombin-responsive peptide (Pep), to obtain Pep-PPC nanocarriers with special mesoporous nanostructures. Subsequently, NO donor BNN6 and thrombolytic drug UK were loaded on the surface and into the mesoporous of Pep-PPC, to get the multifunctional Pep-NO@PPC/UK. In vitro and in vivo results proved that Pep-NO@PPC/UK could effectively recognize and aggregate at the thrombus site via CREKA-mediated active targeting. Then local abundant thrombin cleaved the nanoplatform to release UK. Meanwhile, PDA converted NIR light into heat and synchronously triggered NO release. This transformed the DDS into a "heat-gas" dual propulsion nanomotor in situ, driving deep penetration of UK in thrombus tissue. Under the combined action of UK and PTT, arterial thrombosis rapidly dissolved with relatively low bleeding risk. More importantly, NO generated in situ could prevent re-embolism of blood vessels at the thrombolytic site by inhibiting activated platelet aggregation, ultimately improving vascular reperfusion rate through a combination of attack and defense mode. [ABSTRACT FROM AUTHOR]

Animal models are still used in the research and development of ophthalmic drug products, mainly due to the difficulty in simulating natural physiological conditions with in vitro models, as there is a lack of dynamic protection mechanisms. Therefore, developing alternative ophthalmic models that evaluate drug penetration in the cornea while applying dynamic protection barriers is a contemporary challenge. This study aimed to develop a dynamic ex vivo model using porcine eyes with a simulated lacrimal flow to evaluate the performance of pharmaceutical drug products. A glass donor cell to support a simulated tear flow was designed, optimized, and custom-made. The system was challenged with different formulations (with fluconazole) including excipients with different viscosities (poloxamer 407) and mucoadhesive properties (chitosan). The results were compared to those obtained from a conventional excised cornea model mounted in Franz-type diffusion cells. The dynamic model could differentiate formulations, while the static model did not, overestimating ex vivo drug penetrated amounts. Hence, the dynamic model with simulated tear flow showed to be a simple and promising new alternative method for the drug penetration of ophthalmic formulations that ultimately can reduce the number of animals used in research.

Collagen and hyaluronan are the most abundant components of the extracellular matrix (ECM) and their overexpression in tumors is linked to increased tumor growth and metastasis. These ECM components contribute to a protective tumor microenvironment by supporting a high interstitial fluid pressure and creating a tortuous setting for the convection and diffusion of chemotherapeutic small molecules, antibodies, and nanoparticles in the tumor interstitial space. This review focuses on the research efforts to deplete extracellular collagen with collagenases to normalize the tumor microenvironment. Although collagen synthesis inhibitors are in clinical development, the use of collagenases is contentious and clinically untested in cancer patients. Pretreatment of murine tumors with collagenases increased drug uptake and diffusion 2-10-fold. This modest improvement resulted in decreased tumor growth, but the benefits of collagenase treatment are confounded by risks of toxicity from collagen breakdown in healthy tissues. In this review, we evaluate the published in vitro and in vivo benefits and limitations of collagenase treatment to improve drug delivery.

BackgroundPoly(ADP-ribose) polymerase inhibitors (PARPi), coupled to a DNA damaging agent is a promising approach to treating triple negative breast cancer (TNBC). However, not all patients respond; we hypothesize that non-response in some patients may be due to insufficient drug penetration. As a first step to testing this hypothesis, we quantified and visualized veliparib and carboplatin penetration in mouse xenograft TNBCs and patient blood samples.MethodsMDA-MB-231, HCC70 or MDA-MB-436 human TNBC cells were implanted in 41 beige SCID mice. Low dose (20 mg/kg) or high dose (60 mg/kg) veliparib was given three times daily for three days, with carboplatin (60 mg/kg) administered twice. In addition, blood samples were analyzed from 19 patients from a phase 1 study of carboplatin + PARPi talazoparib. Veliparib and carboplatin was quantified using liquid chromatography-mass spectrometry (LC-MS). Veliparib tissue penetration was visualized using matrix-assisted laser desorption/ionization mass spectrometric imaging (MALDI-MSI) and platinum adducts (covalent nuclear DNA-binding) were quantified using inductively coupled plasma-mass spectrometry (ICP-MS). Pharmacokinetic modeling and Pearson's correlation were used to explore associations between concentrations in plasma, tumor cells and peripheral blood mononuclear cells (PBMCs).ResultsVeliparib penetration in xenograft tumors was highly heterogeneous between and within tumors. Only 35% (CI 95% 26-44%), 74% (40-97%) and 46% (9-37%) of veliparib observed in plasma penetrated into MDA-MB-231, HCC70 and MDA-MB-436 cell-based xenografts, respectively. Within tumors, penetration heterogeneity was larger with the 60 mg/kg compared to the 20 mg/kg dose (RSD 155% versus 255%, P = 0.001). These tumor concentrations were predicted similar to clinical dosing levels, but predicted tumor concentrations were below half maximal concentration values as threshold of response. Xenograft veliparib concentrations correlated positively with platinum adduct formation (R 2 = 0.657), but no PARPi-platinum interaction was observed in patients' PBMCs. Platinum adduct formation was significantly higher in five gBRCA carriers (ratio of platinum in DNA in PBMCs/plasma 0.64% (IQR 0.60-1.16%) compared to nine non-carriers (ratio 0.29% (IQR 0.21-0.66%, P

The abnormal structure of tumor vascular seriously hinders the delivery and deep penetration of drug in tumor therapy. Herein, an integrated and tumor microenvironment (TME)-responsive nanocarrier is designed, which can dilate vessle and improve the drug penetration by in situ releasing nitric oxide (NO). Briefly, S-nitroso-glutathione (GSNO) and curcumin (Cur) were encapsulatd into the Cu-doped zeolite imidazole framework-8 (Cu-ZIF-8) and modified with hyaluronic acid. The nanocarrier degradation in the weakly acidic of TME releases Cu 2+ , then deplete overexpressed intratumourally glutathione and transformed into Cu + , thus disrupting the balance between nicotinamide adenine dinucleotide phosphate and flavin adenine dinucleotide (NADPH/FAD) during the metabolism homeostasis of tumor. The Cu + can generate highly toxic hydroxyl radical through the Fenton-like reaction, enhancing the chemodynamic therapeutic effect. In addition, Cu + also decomposes GSNO to release NO by ionic reduction, leading to vasodilation and increased vascular permeability, significantly promoting the deep penetration of Cur in tumor. Afterwards, the orderly operation of cell cycle is disrupted and arrested in the S-phase to induce tumor cell apoptosis. Deep-hypothermia potentiated 2D/3D fluorescence imaging demonstrated nanocarrier regulated endogenous metabolism homeostasis of tumor. The cascade-catalysed multifunctional nanocarrier provides an approach to treat orthotopic tumor., (© 2024. The Author(s).)

Misfolding and aggregation of specific proteins are associated with liquid-liquid phase separation (LLPS), and these protein aggregates can interfere with normal cellular functions and even lead to cell death, possibly affecting gene expression regulation and cell proliferation. Therefore, understanding the role of LLPS in disease may help to identify new mechanisms or therapeutic targets and provide new strategies for disease treatment. There are several ways to disrupt LLPS, including screening small molecules or small molecule drugs to target the upstream signaling pathways that regulate the LLPS process, selectively dissolve and destroy RNA droplets or protein aggregates, regulate the conformation of mutant protein, activate the protein degradation pathway to remove harmful protein aggregates. Furthermore, harnessing the mechanism of LLPS can improve drug development, including preparing different kinds of drug delivery carriers (microneedles, nanodrugs, imprints), regulating drug internalization and penetration behaviors, screening more drugs to overcome drug resistance and enhance receptor signaling. This review initially explores the correlation between aberrant LLPS and disease, highlighting the pivotal role of LLPS in preparing drug development. Ultimately, a comprehensive investigation into drug-mediated regulation of LLPS processes holds significant scientific promise for disease management., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interest., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Transdermal drug delivery systems are highly appealing as a convenient drug delivery manner applicable to a wide variety of drugs. While most delivery relies on only passive diffusion and suffers low transdermal efficiencies. Ultrasound motivation promotes drug transdermal penetration but still calls for improvement, because only a thin proportion of the ultrasound energy is applied on the drug delivery patch and most ultrasound energy is wasted in deeper portions of biotissues. In this work, we develop a transdermal patch for enhanced drug delivery. The combination of microsized air pockets and the piezoelectric soft structure enable the conversion of an intended proportion of ultrasound energy into electric energy. The intensified drug flow and synergistic ultrasound pressure and electric field function simultaneously to enhance drug transdermal delivery. The delivery efficacy is related to the power of the ultrasound motivation, the size of the microscopic air pockets, and the chemical structure of the drug molecules. The temperature of the patch within the delivery process remains in the safe range, and the mild temperature elevation causes color changes of the thermochromic patch, used to indicate effective ultrasound-patch matching. A model delivery patch for pain release is constructed, and animal experiments indicate that the drug blood concentrations are 100% higher than the delivery using only ultrasound and even more remarkably enhanced when compared to only electric-field-motivated delivery or static delivery without external motivations.

Tao Lu, Jai Prakash Engineered Therapeutics Group, Department of Biomaterials Science and Technology, University of Twente, Enschede, The NetherlandsCorrespondence: Jai PrakashEngineered Therapeutics, Department of Biomaterials Science and Technology, University of Twente, Drienerlolaan 5, Enschede, 7500AE, The NetherlandsTel +31 53 4893096Email j.prakash@utwente.nlAbstract: Pancreatic cancer is one of the most malignant tumors with one of the worst survival rates due to its insidious onset and resistance to therapies. Most therapeutics show a desired anticancer effect in vitro; however, very poor efficacy in vivo because of the limited drug delivery and penetration into pancreatic tumors attributed to the abundance of the tumor stroma, ie, the fibrotic tumor microenvironment surrounding the cancer cells. For a better understanding of the challenges posed by the pancreatic tumor stroma, we outline the key features of the tumor microenvironment. Then we highlight major strategies used to tackle the challenges to improve drug penetration into the tumor and achieve enhanced efficacy (pre)clinically. Furthermore, we describe nanomedicine strategies to modulate the tumor stroma, degrade the extracellular matrix, and co-deliver multi-functional drugs, to improve the chemotherapeutics delivery and penetration into pancreatic tumors.Keywords: pancreatic ductal adenocarcinoma, cancer-associated fibroblasts, tumor stroma, tumor vasculature, drug perfusion, drug penetration

Simple Summary: Scientists have been working on the development of nanomedicine-based tumor therapy, rather than conventional treatment, to treat cancer for several years. Unfortunately, biological barriers hinder the delivery of nanomedicine to tumors. There are different strategies applied by researchers to improve the nanomedicine penetration to tumors, such as the modification of nanoparticle features and controlling the cancer micro-environment. However, complicated cancer micro-environments and delivery problems prevent these approaches from achieving optimal results. Changes in the extra-cellular matrix or blood vessels modify tumor microenvironments in a way that provides improved nanomedicine penetration and distribution but not to an optimal level. Herein, we reviewed the challenges of nanomedicine penetration to tumors along with possible approaches to deal with this concern. Nanomedicine has been under investigation for several years to improve the efficiency of chemotherapeutics, having minimal pharmacological effects clinically. Ineffective tumor penetration is mediated by tumor environments, including limited vascular system, rising cancer cells, higher interstitial pressure, and extra-cellular matrix, among other things. Thus far, numerous methods to increase nanomedicine access to tumors have been described, including the manipulation of tumor micro-environments and the improvement of nanomedicine characteristics; however, such outdated approaches still have shortcomings. Multi-functional convertible nanocarriers have recently been developed as an innovative nanomedicine generation with excellent tumor infiltration abilities, such as tumor-penetrating peptide-mediated transcellular transport. The developments and limitations of nanomedicines, as well as expectations for better outcomes of tumor penetration, are discussed in this review. [ABSTRACT FROM AUTHOR]

Background: Linezolid presents strong antimicrobial activity against multidrug-resistant (MDR) pulmonary tuberculosis (TB), but its application in osteoarticular tuberculosis treatment remains understudied. Our objective was to analyze the bone penetration efficiency of linezolid in osteoarticular TB patients. Methods: Osteoarticular TB patients, treated with 600 mg q 24 h linezolid-containing regimens and undergoing surgery, were prospectively and consecutively enrolled. One dose linezolid was administered before surgery. Blood and bone samples were collected simultaneously during operation, and their linezolid concentrations were then detected using high-performance liquid chromatography-tandem mass spectrometry. Pus samples were subjected to mycobacterial culture and GeneXpert MTB/RIF assay. The minimum inhibition concentrations (MICs) and drug susceptibility testing were performed with the recovered isolates. Results: A total of 36 eligible osteoarticular TB patients were enrolled, including five MDR/rifampicin-resistant cases. All the 12 recovered isolates had MICs ≤0.5 μg/mL for linezolid. Mean concentrations in plasma, collected 100−510 min after the preoperative dosing, were 10.43 ± 4.83 μg/mL (range 3.29−22.26 μg/mL), and median concentrations in bone were 3.93 μg/mL (range 0.61−16.34 μg/mL). The median bone/plasma penetration ratio was 0.42 (range 0.14−0.95 μg/mL). Linezolid concentration in bone had a linear correlation with the drug concentration in plasma (r = 0.7873, p < 0.0001), while plasma concentration could explain 61.98% of the variation of concentration in bone (R2 = 0.6198). Notably, stratification analysis by sampling time demonstrated that samples collected 200−510 min after dosing had very good linear relationships between their bone and plasma concentrations (r = 0.9323). Conclusions: Linezolid penetrates from blood to bone efficiently, and the penetration further stabilizes ∼3 h after dosing.

Abstract Background Despite the highly expected clinical application of nanoparticles (NPs), the translation of NPs from lab to the clinic has been relatively slow. Co-culture 3D spheroids account for the 3D arrangement of tumor cells and stromal components, e.g., cancer-associated fibroblasts (CAFs) and extracellular matrix, recapitulating microenvironment of head and neck squamous cell carcinoma (HNSCC). In the present study, we investigated how the stroma-rich tumor microenvironment affects the uptake, penetration, and photodynamic efficiency of three lipid-based nanoformulations of approved in EU photosensitizer temoporfin (mTHPC): Foslip® (mTHPC in conventional liposomes), drug-in-cyclodextrin-in-liposomes (mTHPC-DCL) and extracellular vesicles (mTHPC-EVs). Results Collagen expression in co-culture stroma-rich 3D HNSCC spheroids correlates with the amount of CAFs (MeWo cells) in individual spheroid. The assessment of mTHPC loading demonstrated that Foslip®, mTHPC-DCL and mTHPC-EVs encapsulated 0.05 × 10− 15 g, 0.07 × 10− 15 g, and 1.3 × 10− 15 g of mTHPC per nanovesicle, respectively. The mid-penetration depth of mTHPC NPs in spheroids was 47.8 µm (Foslip®), 87.8 µm (mTHPC-DCL), and 49.7 µm (mTHPC-EVs), irrespective of the percentage of stromal components. The cellular uptake of Foslip® and mTHPC-DCL was significantly higher in stroma-rich co-culture spheroids and was increasing upon the addition of serum in the culture medium. Importantly, we observed no significant difference between PDT effect in monoculture and co-culture spheroids treated with lipid-based NPs. Overall, in all types of spheroids mTHPC-EVs demonstrated outstanding total cellular uptake and PDT efficiency comparable to other NPs. Conclusions The stromal microenvironment strongly affects the uptake of NPs, while the penetration and PDT efficacy are less sensitive to the presence of stromal components. mTHPC-EVs outperform other lipid nanovesicles due to the extremely high loading capacity. The results of the present study enlarge our understanding of how stroma components affect the delivery of NPs into the tumors.

Topically applied pharmaceuticals in the form of patches that distribute medications for systemic effects at predefined and controlled rates are known as "transdermal drug delivery systems." The main function of TDDS is penetration of drug through skin. It works extremely simple, with the medicine being put within the patch and is placed on the skin. As a result, a consistent concentration of medication remains in the bloodstream for an extended period. They come in variety of forms, including single-layer drugs in adhesives; inter drugs in adhesives, buffers, and matrix systems. The market price of TDDS products is rapidly expanding. More than 35 items have now been authorized for sale in the United States, and roughly 16 active substances have been approved for usage as a TDDS globally. It is a drug delivery system that has a bright future. It helps in reducing use of syringes for administering a wide range of drugs, but the price is an essential aspect to consider because developing countries like India have the world's second-largest population, but TDDS is a secret part of treatment used for the general population due to rising costs. This review article on transdermal drug delivery systems (TDDS) contains information on the transdermal drug delivery system, Advanced development and the evaluation procedure. [ABSTRACT FROM AUTHOR]

Abstract Background High-intensity ultrasound (HIUS) has been increasingly investigated as a possible tool in the treatment of multiple tumor entities. However, there is only little knowledge on the effect of HIUS on the peritoneum. This preliminary study aims to investigate HIUS’ potential for altering the peritoneal surface and potentially improving current treatments for peritoneal metastases. For this purpose, HIUS’ qualitative and quantitative structural effects on the peritoneal tissue were analyzed by means of light, fluorescence and electron microscopy. Methods Proportional sections were cut from the fresh postmortem swine peritoneum. Peritoneal surfaces were covered with a 6 mm thick liquid film of 0.9% NaCl. HIUS was applied in all tissue samples for 0 (control), 30, 60, 120 and 300 s. Peritoneal tissues were analyzed using light-, fluorescence and electron microscopy to detect possible structural changes within the tissues. Results Following HIUS, a superficial disruption of peritoneal tissue was visible in light microscopy, which amplified with increased time of HIUS’ application. Fluorescence microscopy showed both peritoneal and subperitoneal disruption with tissue gaps. Electron microscopy revealed structural filamentation of the peritoneal surface. Conclusion Our data indicate that HIUS causes a wide range of effects on the peritoneal tissue, including the formation of small ruptures in both peritoneal and subperitoneal tissues. However, according to our findings, these disruptions are limited to a microscopical level. Further studies are required to evaluate whether HIUS application can benefit current therapeutic regimens on peritoneal metastases and possibly enhance the efficacy of intraperitoneal chemotherapy.

Recent advancements in ocular drug delivery have led to the introduction of a range of nanotechnology-based systems, such as polymeric nanoparticles, solid lipid nanoparticles, nanostructured lipid carriers, inorganic nanoparticles, niosomes, liposomes, nanosuspensions, dendrimers, nanoemulsions, and microemulsions. These systems enhance drug retention, penetration, bioavailability, and targeted delivery, promising prolonged drug release, and improved patient compliance. However, their interactions with biological systems pose potential toxicity risks, necessitating a careful evaluation of nanoparticle size, shape, surface charge, and coating. Traditional ocular drug delivery methods, like topical applications and injections, face challenges due to anatomical and physiological barriers, leading to frequent dosing and systemic toxicity risks. Nanocarriers offer solutions by improving drug permeation and targeted delivery, yet translating these innovations from research to clinical practice involves overcoming hurdles related to manufacturing scale-up, quality control, regulatory approval, and cost-effectiveness. The quality by design (QbD) framework provides a systematic approach to optimize nanocarrier formulation and process design, ensuring safety and efficacy. Assessing the safety of nanocarriers through in vivo and in vitro studies is crucial for their clinical application. This review explores the use of various nanomedicines in ocular drug delivery, highlighting the current state of ocular medication delivery and considering critical aspects such as scaling up and clinical applications., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Rajan et al.)

Psoriasis, recognized as a chronic inflammatory skin disorder, disrupts immune system functionality. Global estimates by the World Psoriasis Day consortium indicate its impact on approximately 130 million people, constituting 4 to 5 percent of the worldwide population. Conventional drug delivery systems, mainly designed to alleviate psoriasis symptoms, fall short in achieving targeted action and optimal bioavailability due to inherent challenges such as the drug's brief half-life, instability, and a deficiency in ensuring both safety and efficacy. Liposomes, employed in drug delivery systems, emerge as highly promising carriers for augmenting the therapeutic efficacy of topically applied drugs. These small unilamellar vesicles demonstrate enhanced penetration capabilities, facilitating drug delivery through the stratum corneum layer of skin. This comprehensive review article illuminates diverse facets of liposomes as a promising drug delivery system to treat psoriasis. Addressing various aspects such as formulation strategies, encapsulation techniques, and targeted delivery, the review underscores the potential of liposomes in enhancing the efficacy and specificity of psoriasis treatments., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

The systemic use of tranexamic acid (TA) as an oral drug can bring adverse reactions, while intradermal injection leads to pain and a risk of infection. Moreover, it is difficult for highly hydrophilic TA to penetrate the skin barrier that contains lots of hydrophobic lipid compounds, which poses enormous restrictions on its topical application. Current transdermal TA delivery strategies are suffering from low drug load rates, plus their synthesis complexity, time-consumption, etc. adding to the difficulty of TA topical application in clinical therapeutics. To increase the penetration of TA, a novel approach using TA-loaded ZIF-8 (TA@ZIF-8) is developed. The encapsulation efficiency of TA@ZIF-8 reaches ≈25% through physical adsorption and chemical bonding of TA indicates by theoretical simulation and the improved TA penetration is elevated through activating the aquaporin-3 (AQP-3) protein. Additionally, in vivo and in vitro experiments demonstrate the preponderance of TA@ZIF-8 for penetration ability and the advantages in intracellular uptake, minor cytotoxicity, and inhibition of melanogenesis and inflammatory factors. Moreover, clinical trials demonstrate the safety and efficacy of TA@ZIF-8 in the treatment of melasma and rosacea. This work presents a potential topical application of TA, free from the safety concerns associated with systemic drug administration., (© 2024 Wiley‐VCH GmbH.)

The dense extracellular matrix (ECM) in solid tumors, contributed by cancer-associated fibroblasts (CAFs), hinders penetration of drugs and diminishes their therapeutic outcomes. A sequential treatment strategy of remodeling the ECM via a CAF modifier (dasatinib, DAS) is proposed to promote penetration of an immunogenic cell death (ICD) inducer (epirubicin, Epi) via apoptotic vesicles, ultimately enhancing the treatment efficacy against breast cancer. Dendritic poly(oligo(ethylene glycol) methyl ether methacrylate) (POEGMA)-based nanomedicines (poly[OEGMA-Dendron(G2)-Gly-Phe-Leu-Gly-DAS] (P-DAS) and poly[OEGMA-Dendron(G2)-hydrazone-Epi] (P-Epi)) are developed for sequential delivery of DAS and Epi, respectively. P-DAS reprograms CAFs to reduce collagen by downregulating collagen anabolism and energy metabolism, thereby reducing the ECM deposition. The regulated ECM can enhance tumor penetration of P-Epi to strengthen its ICD effect, leading to an amplified antitumor immune response. In breast cancer-bearing mice, this approach alleviates the ECM barrier, resulting in reduced tumor burden and increased cytotoxic T lymphocyte infiltration, and more encouragingly, synergizes effectively with anti-programmed cell death 1 (PD-1) therapy, significantly inhibiting tumor growth and preventing lung metastasis. Furthermore, systemic toxicity is barely detectable after sequential treatment with P-DAS and P-Epi. This approach opens a new avenue for treating desmoplastic tumors by metabolically targeting CAFs to overcome the ECM barrier., (© 2024 Wiley‐VCH GmbH.)

The effects of dendron side chains in polymeric conjugates on tumor penetration and antigen presentation are systematically examined. Three polymer-gemcitabine (Gem) conjugates (pG0-Gem, pG1-Gem, pG2-Gem) are designed and prepared. The pG2-Gem conjugate uniquely binds to the mitochondria of tumor cells, thus regulating mitochondrial dynamics. The interaction between the pG2-Gem conjugate and the mitochondria promotes great penetration and accumulation of the conjugate at the tumor site, resulting in pronounced antitumor effects in an animal model. Such encouraging therapeutic effects can be ascribed to immune modulation since MHC-1 antigen presentation is significantly enhanced due to mitochondrial fusion and mitochondrial metabolism alteration after pG2-Gem treatment. Crucially, the drug-free dendronized polymer, pG2, is identified to regulate mitochondrial dynamics, and the regulation is independent of the conjugated Gem. Furthermore, the combination of pG2-Gem with anti-PD-1 antibody results in a remarkable tumor clearance rate of 87.5% and a prolonged survival rate of over 150 days, demonstrating the potential of dendronized polymers as an innovative nanoplatform for metabolic modulation and synergistic tumor immunotherapy., (© 2024 Wiley‐VCH GmbH.)

This study aims to develop a multiscale method that will help improve drug delivery systems. A finite volume heterogeneous multiscale method (FV-HMM) is propounded to model mass transport by considering cell scale heterogeneity in the biological tissues. The partition phenomenon is included in the mass transport model. A new upscaling technique has been devised to evaluate the effective mass transport at the macro level. An interface method based on alternating direction implicit scheme is used to solve the microscale models. FV-HMM is used to study the tissue penetration efficacy of drug nanoparticles. Numerical experiments are performed with different parameters, and it is concluded that partition phenomenon and particle size are the important factors on tissue penetration efficacy of nanoparticles in drug delivery. Also, FV-HMM is used to determine the biological cell geometry impact on drug penetration at the tissue scale. [ABSTRACT FROM AUTHOR]

• Linezolid in bone of osteoarticular tuberculosis patient was detected, which had rarely been reported. • A ratio between blood/bone linezolid concentrations of 0.42 was identified. • Samples collected 200–510 mins after dosing had very good linear relationship between bone and plasma concentrations (r = 0.9323). • Bone linezolid concentration prediction could be accurately performed with known plasma concentration during 200–510 mins after dosing. Linezolid presents strong antimicrobial activity against multidrug-resistant (MDR) pulmonary tuberculosis (TB), but its application in osteoarticular tuberculosis treatment remains understudied. Our objective was to analyze the bone penetration efficiency of linezolid in osteoarticular TB patients. Osteoarticular TB patients, treated with 600 mg q 24 h linezolid-containing regimens and undergoing surgery, were prospectively and consecutively enrolled. One dose linezolid was administered before surgery. Blood and bone samples were collected simultaneously during operation, and their linezolid concentrations were then detected using high-performance liquid chromatography-tandem mass spectrometry. Pus samples were subjected to mycobacterial culture and GeneXpert MTB/RIF assay. The minimum inhibition concentrations (MICs) and drug susceptibility testing were performed with the recovered isolates. A total of 36 eligible osteoarticular TB patients were enrolled, including five MDR/rifampicin-resistant cases. All the 12 recovered isolates had MICs ≤0.5 μg/mL for linezolid. Mean concentrations in plasma, collected 100−510 min after the preoperative dosing, were 10.43 ± 4.83 μg/mL (range 3.29−22.26 μg/mL), and median concentrations in bone were 3.93 μg/mL (range 0.61−16.34 μg/mL). The median bone/plasma penetration ratio was 0.42 (range 0.14−0.95 μg/mL). Linezolid concentration in bone had a linear correlation with the drug concentration in plasma (r = 0.7873, p < 0.0001), while plasma concentration could explain 61.98% of the variation of concentration in bone (R2 = 0.6198). Notably, stratification analysis by sampling time demonstrated that samples collected 200−510 min after dosing had very good linear relationships between their bone and plasma concentrations (r = 0.9323). Linezolid penetrates from blood to bone efficiently, and the penetration further stabilizes ∼3 h after dosing. [ABSTRACT FROM AUTHOR]

Background: Despite the highly expected clinical application of nanoparticles (NPs), the translation of NPs from lab to the clinic has been relatively slow. Co-culture 3D spheroids account for the 3D arrangement of tumor cells and stromal components, e.g., cancer-associated fibroblasts (CAFs) and extracellular matrix, recapitulating microenvironment of head and neck squamous cell carcinoma (HNSCC). In the present study, we investigated how the stroma-rich tumor microenvironment affects the uptake, penetration, and photodynamic efficiency of three lipid-based nanoformulations of approved in EU photosensitizer temoporfin (mTHPC): Foslip® (mTHPC in conventional liposomes), drug-in-cyclodextrin-in-liposomes (mTHPC-DCL) and extracellular vesicles (mTHPC-EVs). Results: Collagen expression in co-culture stroma-rich 3D HNSCC spheroids correlates with the amount of CAFs (MeWo cells) in individual spheroid. The assessment of mTHPC loading demonstrated that Foslip®, mTHPC-DCL and mTHPC-EVs encapsulated 0.05 × 10− 15 g, 0.07 × 10− 15 g, and 1.3 × 10− 15 g of mTHPC per nanovesicle, respectively. The mid-penetration depth of mTHPC NPs in spheroids was 47.8 µm (Foslip®), 87.8 µm (mTHPC-DCL), and 49.7 µm (mTHPC-EVs), irrespective of the percentage of stromal components. The cellular uptake of Foslip® and mTHPC-DCL was significantly higher in stroma-rich co-culture spheroids and was increasing upon the addition of serum in the culture medium. Importantly, we observed no significant difference between PDT effect in monoculture and co-culture spheroids treated with lipid-based NPs. Overall, in all types of spheroids mTHPC-EVs demonstrated outstanding total cellular uptake and PDT efficiency comparable to other NPs. Conclusions: The stromal microenvironment strongly affects the uptake of NPs, while the penetration and PDT efficacy are less sensitive to the presence of stromal components. mTHPC-EVs outperform other lipid nanovesicles due to the extremely high loading capacity. The results of the present study enlarge our understanding of how stroma components affect the delivery of NPs into the tumors. [ABSTRACT FROM AUTHOR]

The development of curative treatment for glioblastoma has been extremely challenging. Chemotherapeutic agents that have seemed promising have failed in clinical trials. Drugs that can successfully target cancer cells within the brain must first traverse the brain interstitial fluid. Cerebral microdialysis (CMD) is an invasive technique in which interstitial fluid can be directly sampled. CMD has primarily been used clinically in the setting of head trauma and subarachnoid hemorrhage. Our goal was to review the techniques, principles, and new data pertaining to CMD to highlight its use in neuro-oncology. We conducted a literature search using the PubMed database and selected studies in which the investigators had used CMD in either animal brain tumor models or clinical trials. The references were reviewed for additional information. Studies of CMD have shown its importance as a neurosurgical technique. CMD allows for the collection of pharmacokinetic data on drug penetrance across the blood–brain barrier and metabolic data to characterize the response to chemotherapy. Although no complications have been reported, the current CMD technique (as with any procedure) has risks and limitations, which we have described in the present report. Animal CMD experiments have been used to exclude central nervous system drug candidates from progressing to clinical trials. At present, patients undergoing CMD have been monitored in the intensive care unit, owing to the requisite tethering to the apparatus. This can be expected to change soon because of advances in microminiaturization. CMD is an extremely valuable, yet underused, technique. Future CMD applications will have central importance in assessing drug delivery to tumor cells in vivo, allowing a pathway to successful therapy for malignant brain tumors. Depiction of a cerebral microdialysis probe tip in the brain with infiltrating tumor cells, showing in flow of perfusate and out flow of dialysate (purple arrows), with drug equilibration occurring across the semipermeable membrane (green arrows). Light green spheres indicate the drug; tumor cells are indicated in dark green. [ABSTRACT FROM AUTHOR]

As the intertissue delivery of hydrophobic temoporfin (mTHPC) remains inefficient, we propose the use of cyclodextrin-based nanosponges as a smart, advanced system for improved mTHPC delivery. Recently, we demonstrated that cyclodextrins (CDs) allow mTHPC to penetrate into tumor spheroids via a nanoshuttle mechanism. However, the CD complexes were very sensitive to the dilution, thus limiting their translation in vivo. Hypercrosslinked CD monomers in a three-dimensional network (namely, CD nanosponges), however, may form both inclusion and non-inclusion complexes with drug molecules, providing controlled release and prolonged exposure to the drug. In the present work, we demonstrate that epichlorohydrin-crosslinked CD nanosponges based on β-CD (βCDp) and carboxymethyl-β-CD (CMβCDp) monomers efficiently encapsulated mTHPC. We calculated the apparent binding constants between mTHPC and CD polymers (K = (6.3–8.8) × 106 M−1 and K = (1.2–1.7) × 106 M−1 for βCDp and CMβCDp, respectively) using fluorescence titration curve fitting. The encapsulation of mTHPC in a CD polymer matrix had slower photosensitizer (PS) release compared to monomer CD units, providing deep penetration of mTHPC in 3D tumor spheroids in a concentration-dependent manner. However, the improvement of mTHPC penetration in 3D human pharynx squamous cell carcinoma (FaDu) spheroids using CD polymers was strongly accompanied by the inhibition of PS cellular uptake, demonstrating the delicate balance between the accumulation and the penetration of PS in FaDu spheroids. In summary, mTHPC-loaded CD nanosponges are a strong candidate for further in vivo study in preclinical models, which could be considered as an advanced smart system for mTHPC delivery. [ABSTRACT FROM AUTHOR]

Background: High-intensity ultrasound (HIUS) has been increasingly investigated as a possible tool in the treatment of multiple tumor entities. However, there is only little knowledge on the effect of HIUS on the peritoneum. This preliminary study aims to investigate HIUS' potential for altering the peritoneal surface and potentially improving current treatments for peritoneal metastases. For this purpose, HIUS' qualitative and quantitative structural effects on the peritoneal tissue were analyzed by means of light, fluorescence and electron microscopy.Methods: Proportional sections were cut from the fresh postmortem swine peritoneum. Peritoneal surfaces were covered with a 6 mm thick liquid film of 0.9% NaCl. HIUS was applied in all tissue samples for 0 (control), 30, 60, 120 and 300 s. Peritoneal tissues were analyzed using light-, fluorescence and electron microscopy to detect possible structural changes within the tissues.Results: Following HIUS, a superficial disruption of peritoneal tissue was visible in light microscopy, which amplified with increased time of HIUS' application. Fluorescence microscopy showed both peritoneal and subperitoneal disruption with tissue gaps. Electron microscopy revealed structural filamentation of the peritoneal surface.Conclusion: Our data indicate that HIUS causes a wide range of effects on the peritoneal tissue, including the formation of small ruptures in both peritoneal and subperitoneal tissues. However, according to our findings, these disruptions are limited to a microscopical level. Further studies are required to evaluate whether HIUS application can benefit current therapeutic regimens on peritoneal metastases and possibly enhance the efficacy of intraperitoneal chemotherapy. [ABSTRACT FROM AUTHOR]

Abstract Background Poly(ADP-ribose) polymerase inhibitors (PARPi), coupled to a DNA damaging agent is a promising approach to treating triple negative breast cancer (TNBC). However, not all patients respond; we hypothesize that non-response in some patients may be due to insufficient drug penetration. As a first step to testing this hypothesis, we quantified and visualized veliparib and carboplatin penetration in mouse xenograft TNBCs and patient blood samples. Methods MDA-MB-231, HCC70 or MDA-MB-436 human TNBC cells were implanted in 41 beige SCID mice. Low dose (20 mg/kg) or high dose (60 mg/kg) veliparib was given three times daily for three days, with carboplatin (60 mg/kg) administered twice. In addition, blood samples were analyzed from 19 patients from a phase 1 study of carboplatin + PARPi talazoparib. Veliparib and carboplatin was quantified using liquid chromatography–mass spectrometry (LC-MS). Veliparib tissue penetration was visualized using matrix-assisted laser desorption/ionization mass spectrometric imaging (MALDI-MSI) and platinum adducts (covalent nuclear DNA-binding) were quantified using inductively coupled plasma–mass spectrometry (ICP-MS). Pharmacokinetic modeling and Pearson’s correlation were used to explore associations between concentrations in plasma, tumor cells and peripheral blood mononuclear cells (PBMCs). Results Veliparib penetration in xenograft tumors was highly heterogeneous between and within tumors. Only 35% (CI 95% 26–44%), 74% (40–97%) and 46% (9–37%) of veliparib observed in plasma penetrated into MDA-MB-231, HCC70 and MDA-MB-436 cell-based xenografts, respectively. Within tumors, penetration heterogeneity was larger with the 60 mg/kg compared to the 20 mg/kg dose (RSD 155% versus 255%, P = 0.001). These tumor concentrations were predicted similar to clinical dosing levels, but predicted tumor concentrations were below half maximal concentration values as threshold of response. Xenograft veliparib concentrations correlated positively with platinum adduct formation (R 2 = 0.657), but no PARPi–platinum interaction was observed in patients’ PBMCs. Platinum adduct formation was significantly higher in five gBRCA carriers (ratio of platinum in DNA in PBMCs/plasma 0.64% (IQR 0.60–1.16%) compared to nine non-carriers (ratio 0.29% (IQR 0.21–0.66%, P

Objective: To establish a 3-dimensional tuberculosis spheroid model for studying the formation and characteristics of tuberculous granuloma in vivo ., Methods: Human myeloid leukemia mononuclear THP-1 cells and Bacillus Calmette-Guerin (BCG) were mixed in a 3D cell culture plate and co-cultured in the presence of PMA for 3 days. The growth of the spheroid was examined every 24 h, and the distribution of bacteria, cell survival rate, transformation of the monocytes into macrophages, and penetration of fluorescently labeled nanoparticles into the cell spheroids and tuberculosis spheroids were observed using confocal laser scanning microscopy. The BCG and cell architecture within the 3D tuberculosis spheroid was observed using transmission electron microscopy. Image-iT TM red hypoxia probe, H 2 O 2 test kit, and a waterproof pen PH meter were used to detect the differences in the microenvironment between BCG-infected and non-infected 3D tuberculous spheroids. The utility of this 3D tuberculous spheroids for assessing antibiotic effects of rifampicin and levofloxacin was evaluated by plate colony counting., Results: In the cell-bacterial suspensions, stable 3-D tuberculous spheroids (50-200 μm) occurred slowly, in which the cells adhered tightly with numerous bacteria in the center, and necrotic cells and monocytederived macrophages were seen within the spheroids. Drug penetration was difficult in the 3D tuberculous spheroids as compared with the non-infected cell spheroids. Transmission electron microscopy revealed the presence of cell necrosis and a large number of BCG in the macrophages in the tuberculous spheroids. The tuberculosis spheroid had a more hypoxic microenvironment than the non-infected cell spheroids with higher H 2 O 2 content and nearly a neutral PH. The tuberculous spheroid model was capable of evaluating the efficacy of anti-tuberculosis drugs, and among them rifampicin showed a stronger antibacterial effect., Conclusion: The 3-D tuberculous spheroid model established in this study provides a useful platform for studies of tuberculous granuloma.

The present ex vivo study was performed to analyze the impact of high intensity ultrasound (HIUS) on penetration depth and particle stability of liposomal doxorubicin (LD) on the peritoneal surface. Fresh post mortem swine peritoneum was cut into proportional sections and subjected to a previously established ex vivo model of pressurized intraperitoneal aerosol chemotherapy (PIPAC). Samples were treated with 50 ml NaCl (0.9%) containing 3 mg LD via PIPAC or lavage. In both groups, half of the samples received additional HIUS treatment. Samples treated via PIPAC were covered with a 30-mm-thick abdominal muscle wall tissue, fatty tissue and skin, followed by transcutaneous HIUS. Samples administered with LD via lavage received close-range contact HIUS. Doxorubicin tissue penetration was measured using fluorescence microscopy on frozen sections. Liposomal integrity on peritoneal surfaces was measured via electron microscopy (EM). Mean penetration rates of doxorubicin were significantly higher with HIUS in combination with PIPAC or lavage compared with PIPAC alone (P<0.001) or lavage alone (P<0.00001). LD was not detected on the peritoneal surface via EM analysis in either group following HIUS. The present data suggested that HIUS may be a feasible application that can facilitate the release of doxorubicin from its liposomal envelope. HIUS was effective in both close-range, in contact with the samples, and through the abdominal wall. The present approach may be used in the future for both endoscopic and open lavage of the peritoneal cavity with LD in intraperitoneal chemotherapeutic applications such as hyperthermic intraperitoneal chemotherapy or PIPAC. [ABSTRACT FROM AUTHOR]

We recently constructed a multicellular spheroid model of pancreatic tumor based on a triple co-culture of cancer cells, fibroblasts and endothelial cells and characterized by the presence of fibronectin, an important component of the tumor extracellular matrix. By combining cancer cells and stromal components, this model recreates in vitro the three-dimensional (3D) architecture of solid tumors. In this study, we used these hetero-type spheroids as a tool to assess the penetration of doxorubicin (used as a model drug) through the whole tumor mass either in a free form or loaded into polymer nanoparticles (NPs), and we investigated whether microscopy images, acquired by Confocal Laser Scanning Microscopy (CLSM) and Light Sheet Fluorescence Microscopy (LSFM), would be best to provide reliable information on this process. Results clearly demonstrated that CLSM was not suitable to accurately monitor the diffusion of small molecules such as the doxorubicin. Indeed, it only allowed to scan a layer of 100 µm depth and no information on deeper layers could be available because of a progressive loss of the fluorescence signal. On the contrary, a complete 3D tomography of the hetero-type multicellular tumor spheroids (MCTS) was obtained by LSFM and multi-view image fusion which revealed that the fluorescent molecule was able to reach the core of spheroids as large as 1 mm in diameter. However, no doxorubicin-loaded polymer nanoparticles were detected in the spheroids, highlighting the challenge of nanomedicine delivery through biological barriers. Overall, the combination of hetero-type MCTS and LSFM allowed to carry out a highly informative microscopic assessment and represents a suitable approach to precisely follow up the drug penetration in tumors. Accordingly, it could provide useful support in the preclinical investigation and optimization of nanoscale systems for drug delivery to solid tumors. [ABSTRACT FROM AUTHOR]

Systemic chemotherapy is one of the main anticancer treatments used for most kinds of clinically diagnosed tumors. However, the efficacy of these drugs can be hampered by the physical attributes of the tumor tissue, such as tortuous vasculature, dense and fibrous extracellular matrix, irregular cellular architecture, tumor metabolic gradients, and non-uniform expression of the cell membrane receptors. This can impede the transport of therapeutic agents to tumor cells in sufficient quantities. In addition, tumor microenvironments undergo dynamic spatio-temporal changes during tumor progression and treatment, which can also obstruct drug efficacy. To examine ways to improve drug delivery on a cell-to-tissue scale (single-cell pharmacology), we developed the microscale pharmacokinetics/pharmacodynamics (microPKPD) modeling framework. Our model is modular and can be adjusted to include only the mathematical equations that are crucial for a biological problem under consideration. This modularity makes the model applicable to a broad range of pharmacological cases. As an illustration, we present two specific applications of the microPKPD methodology that help to identify optimal drug properties. The hypoxia-activated drugs example uses continuous drug concentrations, diffusive–advective transport through the tumor interstitium, and passive transmembrane drug uptake. The targeted therapy example represents drug molecules as discrete particles that move by diffusion and actively bind to cell receptors. The proposed modeling approach takes into account the explicit tumor tissue morphology, its metabolic landscape and/or specific receptor distribution. All these tumor attributes can be assessed from patients' diagnostic biopsies; thus, the proposed methodology can be developed into a tool suitable for personalized medicine, such as neoadjuvant chemotherapy. [ABSTRACT FROM AUTHOR]

Abstract Development of buccal application forms is gaining increasing interest in recent years, mostly driven by the insight that enabling formulations may help to overcome limitations as well as the need for patient-oriented medicines. A key characteristic of dosage forms is whether they can grant absorption of therapeutically relevant doses across the limited absorption area in the mouth and realistic time window. Despite the generally accepted paradigm to replace or at least reduce animal experiments, current transport studies towards oromucosal drug delivery still are dominated by in vivo or ex vivo animal studies. Only few groups have published pioneering transport experiments with alternative models avoiding the use of animals. The few studies indicate that there is increasing justification for the use of artificial membranes to replace the classical cell- and tissue-based systems. The artificial membranes need to be biomimetic and distinguish transport kinetics of dissociation states and molecule flexibility. It appears that dissociation states may be distinguished by silicone membranes, as well as by phospholipid based models (PAMPA variants and Permeapad®). Regarding other molecule properties such as flexibility, data are available demonstrating excellent IVIVR. Aim of the current review is to make the scientific community dealing with oromucosal drug formulation development aware of the opportunities provided by non-cellular artificial membranes. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

α-Mangostin (MGS) exhibits various pharmacological activities, including antioxidant, anticancer, antibacterial, and anti-inflammatory properties. However, its low water solubility is the major obstacle for its use in pharmaceutical applications. To increase the water solubility of MGS, complex formation with beta-cyclodextrins (βCDs), particularly with the native βCD and/or its derivative 2,6-dimethyl-β-CD (DMβCD) is a promising technique. Although there have been several reports on the adsorption of βCDs on the lipid bilayer, the release of the MGS/βCDs inclusion complex through the biological membrane remains unclear. In this present study, the release the MGS from the two different βCDs (βCD and DMβCD) across the lipid bilayer was investigated. Firstly, the adsorption of the free MGS, free βCDs, and inclusion complex formation was studied by conventional molecular dynamics simulation. The MGS in complex with those two βCDs was able to spontaneously release free MGS into the inner membrane. However, both MGS and DMβCD molecules potentially permeated into the deeper region of the interior membrane, whereas βCD only adsorbed at the outer membrane surface. The interaction between secondary rim of βCD and the 1-palmitoeyl-2-oleoyl-glycero-3-phosphocholine (POPC) phosphate groups showed the highest number of hydrogen bonds (up to 14) corresponding to the favorable location of βCD on the POPC membrane. Additionally, the findings suggested that electrostatic energy was the main driving force for βCD adsorption on the POPC membrane, while van der Waals interactions played a predominant role in DMβCD adsorption. The release profile of MGS from the βCDs pocket across the lipid bilayer exhibited two energy minima along the reaction coordinate associated with the permeation of the MGS molecule into the deeper region of the POPC membrane.