Lymphatic Uptake Research Articles

A lymphatic-absorbed multi-targeted kinase inhibitor for myelofibrosis therapy

Activation of compensatory signaling nodes in cancer often requires combination therapies that are frequently plagued by dose-limiting toxicities. Intestinal lymphatic drug absorption is seldom explored, although reduced toxicity and sustained drug levels would be anticipated to improve systemic bioavailability. A potent orally bioavailable multi-functional kinase inhibitor (LP-182) is described with intrinsic lymphatic partitioning for the combined targeting of phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) signaling pathways without observable toxicity. We demonstrate selectivity and therapeutic efficacy through reduction of downstream kinase activation, amelioration of disease phenotypes, and improved survival in animal models of myelofibrosis. Our further characterization of synthetic and physiochemical properties for small molecule lymphatic uptake will support continued advancements in lymphatropic therapy for altering disease trajectories of a myriad of human disease indications.

Subcutaneous delivery of a dendrimer-BH3 mimetic improves lymphatic uptake and survival in lymphoma.

As a malignant tumour of lymphatic origin, B-cell lymphoma represents a significant challenge for drug delivery, where effective therapies must access malignant cells in the blood, organs and lymphatics while avoiding off-target toxicity. Subcutaneous (SC) administration of nanomedicines allows preferential access to both the lymphatic and blood systems and may therefore provide a route to enhanced drug exposure to lymphomas. Here we examine the impact of SC dosing on lymphatic exposure, pharmacokinetics (PK), and efficacy of AZD0466, a small molecule dual Bcl-2/Bcl-xL inhibitor conjugated to a 'DEP®' G5 poly-l-lysine dendrimer. PK studies reveal that the plasma half-life of the dendrimer-drug conjugate is 8-times longer than that of drug alone, providing evidence of slow release from the circulating dendrimer nanocarrier. The SC dosed construct also shows preferential lymphatic transport, with over 50% of the bioavailable dose recovered in thoracic lymph. Increases in dose (up to 400mg/kg) are well tolerated after SC administration and studies in a model of disseminated lymphoma in mice show that high dose SC treatment outperforms IV administration using doses that lead to similar total plasma exposure (lower peak concentrations but extended exposure after SC). These data show that the DEP® dendrimer can act as a circulating drug depot accessing both the lymphatic and blood circulatory systems. SC administration improves lymphatic exposure and facilitates higher dose administration due to improved tolerability. Higher dose SC administration also results in improved efficacy, suggesting that drug delivery systems that access both plasma and lymph hold significant potential for the treatment of haematological cancers where lymphatic and extranodal dissemination are poor prognostic factors.

Engineered Nanoscale Lipid-Based Formulation as Potential Enhancer of Gefitinib Lymphatic Delivery: Cytotoxicity and Apoptotic Studies Against the A549 Cell Line.

The present study aimed to engineer a nanoscale lipid-based lymphatic drug delivery system with D-α-Tocopherol polyethylene glycol 1000 succinate to combat the lymphatic metastasis of lung cancer. The nanoscale lipid-based systems including GEF-SLN, GEF-NLC, and GEF-LE were prepared and pharmaceutically characterized. In addition, the most stable formulation (GEF-NLC) was subjected to an in vitro release study. Afterward, the optimized GEF-NLC was engineered with TPGS (GEF-TPGS-NLC) and subjected to in vitro cytotoxicity, and apoptotic studies using the A549 cells line as a surrogate model for lung cancer. The present results revealed that particle size and polydispersity index of freshly prepared formulations were ranging from 198 to 280 nm and 0.106 to 0.240, respectively, with negative zeta potential ranging from − 14 to − 27.6.mV. An in vitro release study showed that sustained drug release was attained from GEF-NLC containing a high concentration of lipid. In addition, GEF-NLC and GEF-TPGS-NLC showed remarkable entrapment efficiency above 89% and exhibited sustained release profiles. Cytotoxicity showed that IC50 of pure GEF was 11.15 μg/ml which decreased to 7.05 μg/ml for GEF-TPGS-NLC. The apoptotic study revealed that GEF-TPGS-NLC significantly decreased the number of living cells from 67 to 58% when compared with pure GEF. The present results revealed that the nanoscale and lipid composition of the fabricated SLN, NLC, and LE could mediate the lymphatic uptake of GEF to combat the lymphatic tumor metastasis. Particularly, GEF-TPGS-NLC is a promising LDDS to increase the therapeutic outcomes of GEF during the treatment of metastatic lung cancer.Graphical abstract

Abstract 3936: Orally bioavailable 'lymphatropic' kinase inhibitors

Abstract Cancer signaling pathways can readily adapt to evade therapy through intrinsic resistance or compensatory mechanisms driving a resistant state. The prominence of oncogenic kinase signaling in a multitude of cancer types has inspired development of molecularly targeted drugs, facilitating combination treatment strategies designed to overcome adaptations such as signaling crosstalk and activation of downstream effectors. Treatments using inhibitor combinations, however, remain a challenge as clinical trials have been fraught with dose-limiting toxicities. Avoidance of hepatic first-pass metabolism by transport and sequestration into mesenteric gastrointestinal lymphatic vessels may improve drug exposure and reduce dose-limiting toxicities often observed in combination therapy studies. Despite potential advantages, lymphatically directed kinase inhibitors have remained unexplored due in part to limited understanding of the physicochemical properties required for lymphatic uptake of small molecules. We demonstrate a first-in-class series of orally bioavailable small molecule kinase inhibitors which are intrinsically ‘lymphatropic’, undergoing lymphatic absorption to achieve sustained circulatory drug levels and therapeutic benefit, with no observable toxicity. Single agent multifunctional inhibitors of high-value targets (MEK/PI3K, MEK/PI3K/mTOR, & MEK/mTOR) were designed and synthesized. Compounds had unique physiochemical properties, demonstrating high lymphatic uptake in a mesenteric lymphatic vessel cannulation model and in isolated lymph nodes extracts. Pharmacokinetic studies in mice following oral administration revealed that sustained plasma blood levels were achieved within the therapeutic window for up to 24 hours. Oral bioavailability in mice was found to be 80-85% of drug administered and was constant over a single-dose range study (100 to 1,000 mg/kg). On-target in vitro and in vivo inhibition of activated MEK and PI3K was also demonstrated, revealing high potency of both the parent molecule and therapeutically active metabolites. Together, these studies revealed that lymphatic sequestration of orally dosed compounds serves to provide a reservoir that circumvents pharmacotoxicity through controlled physiological drug release into the systemic circulation and avoidance of first-pass hepatic metabolism. This platform provides a template for further development of additional lymphatropic small molecule inhibitors presenting opportunities in which multi-targeted cancer treatment options can now be evaluated. Exciting new therapeutic prospects offered by lymphatropic agent development is anticipated to transform treatment options for a wide variety of cancer types such as metastasis and lymphoma along with a myriad of other diseases including autoimmune disorders. Citation Format: Brian D. Ross, Youngsoon Jang, Amanda Welton, Christopher A. Bonham, Kevin Heist, Lucas McDonald, Gary D. Luker, Thomas L. Chenevert, Marcian Van Dort. Orally bioavailable 'lymphatropic' kinase inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3936.

Development and validation of UPLC-MS/MS method for in vitro quantitative analysis of pyrazinamide in lipid core-shell nanoarchitectonics for improved metabolic stability

Abstract Pyrazinamide (PZA), a medication for tuberculosis, has high aqueous solubility and low permeability, undergoes extensive liver metabolism, and exhibits liver toxicity through its metabolites. To avoid this, PZA in lipid core-shell nanoarchitectonics has been formulated to target lymphatic uptake and provide metabolic stability to the incorporated drug. The UPLC-MS/MS method for reliable in vitro quantitative analysis of pyrazinamide (PZA) in lipid core-shell nanoarchitectonics as per ICH guidance was developed and validated using the HILIC column. The developed UPLC-MS/MS method is a simple, precise, accurate, reproducible, and sensitive method for the estimation of PZA in PZA-loaded lipid core-shell nanoarchitectonics for the in vitro determination of % entrapment efficiency, % loading of pyrazinamide, and microsomal stability of lipid core-shell nanoarchitectonics in human liver microsomes. The % entrapment efficiency was found to be 42.72% (±12.60). Lipid nanoarchitectonics was found to be stable in human liver microsomes, where %QH was found to be 6.20%, that is, low clearance. Thus, this formulation is suitable for preventing PZA-mediated extensive liver metabolism. These findings are relevant for the development of other lipid-mediated, suitable, stable nanoformulations containing PZA through various in vitro methods.

F18-FDG PET/CT imaging early predicts pathologic complete response to induction chemoimmunotherapy of locally advanced head and neck cancer: preliminary single-center analysis of the checkrad-cd8 trial

AimIn the CheckRad-CD8 trial patients with locally advanced head and neck squamous cell cancer are treated with a single cycle of induction chemo-immunotherapy (ICIT). Patients with pathological complete response (pCR) in the re-biopsy enter radioimmunotherapy. Our goal was to study the value of F-18-FDG PET/CT in the prediction of pCR after induction therapy.MethodsPatients treated within the CheckRad-CD8 trial that additionally received FDG- PET/CT imaging at the following two time points were included: 3–14 days before (pre-ICIT) and 21–28 days after (post-ICIT) receiving ICIT. Tracer uptake in primary tumors (PT) and suspicious cervical lymph nodes (LN +) was measured using different quantitative parameters on EANM Research Ltd (EARL) accredited PET reconstructions. In addition, mean FDG uptake levels in lymphatic and hematopoietic organs were examined. Percent decrease (Δ) in FDG uptake was calculated for all parameters. Biopsy of the PT post-ICIT acquired after FDG-PET/CT served as reference. The cohort was divided in patients with pCR and residual tumor (ReTu).ResultsThirty-one patients were included. In ROC analysis, ΔSUVmax PT performed best (AUC = 0.89) in predicting pCR (n = 17), with a decline of at least 60% (sensitivity, 0.77; specificity, 0.93). Residual SUVmax PT post-ICIT performed best in predicting ReTu (n = 14), at a cutpoint of 6.0 (AUC = 0.91; sensitivity, 0.86; specificity, 0.88). Combining two quantitative parameters (ΔSUVmax ≥ 50% and SUVmax PT post-ICIT ≤ 6.0) conferred a sensitivity of 0.81 and a specificity of 0.93 for determining pCR. Background activity in lymphatic organs or uptake in suspected cervical lymph node metastases lacked significant predictive value.ConclusionFDG-PET/CT can identify patients with pCR after ICIT via residual FDG uptake levels in primary tumors and the related changes compared to baseline. FDG-uptake in LN + had no predictive value.Trial registryClinicalTrials.gov identifier: NCT03426657.

Enhanced dissolution and bioavailability of revaprazan using self-nanoemulsifying drug delivery system

A self-nanoemulsifying drug delivery system (SNEDDS) was developed to enhance the dissolution and oral bioavailability (BA) of revaprazan (RVP). Various SNEDDSs containing 200 mg of RVP were formulated using Capmul MCM, Tween 80, and Brij L4, and they were characterized according to their size, polydispersity index, and dissolution behavior. Dissolution rates of all SNEDDS formulations significantly (p < 0.05) improved with the formation of nanoemulsion with monodispersity. Formulation D resulted in RVP dissolution exceeding 70% at 2 h. Compared to raw RVP, SNEDDS exhibited a 4.8- to 7.4-fold improved effective permeability coefficient (Peff) throughout the intestine in the in situ single pass intestinal permeability study and a 5.1-fold increased oral BA in the in vivo oral absorption assessment in rats. To evaluate the degree of lymphatic uptake, cycloheximide (CYC), a chylomicron flowing blocker, was pretreated prior to the experiment. This pretreatment barely affected the absorption of raw RVP; however, it greatly influenced the absorption of SNEDDS, resulting in an approximately 40% reduction in both the Peff value and oral BA representing lymphatic transport. Thus, we suggest that the SNEDDS formulation is a good candidate for improving oral absorption of RVP through enhanced lymphatic uptake.

P2. FAT GRAFT PULMONARY EMBOLISM: IN FAVOUR OF A LYMPHATIC ROUTE

PURPOSE: Fat Pulmonary Embolism Syndrome (F-PES) complicates high-volume fat grafting. Adipocyte disruption generates triglyceride (TGC) oil dispersed in lipoaspirate (lipocrit). TGC plasma concentration ([TGC]p) was compared with lipocrit during liposuction-lipografting procedures. 1 buttock grafting case suffered a F-PES that required ICU support. METHODS: n=27 (19 breast, 8 buttocks) lipocrit recorded and ([TGC]p) measured in peripheral blood samples preoperatively, intra and 24h postoperatively. F-PES patient underwent right subclavian vein access (SVC) and Inferior Vena Cava (IVC) at ICU admission RESULTS: Lipocrit (200-600 cc graft volume) ranged 19-27%.Peripheral [TGC]p pre-, intra- post- and at 24h displayed no significant differences for all cases. In the F-PES case, SVC drawn [TGC]p was 7-fold higher than that from simultaneously drawn IVC or peripheral samples and returned to normal peripheral levels 48 h later. These unexpected data prompted measurement of:Critical Micelle Concentration (CMC) of fat graft oil when mixed in either lymphatic (chylous, CMCc) or plasmatic (CMCp) fluids. CMCp was consistently higher than CMCc (CMCc=110 mg/dL, CMCp=320 mg/dL, n=17, P<0.001).Interstitial Pressures (IP) both intramuscular (im) and subcutaneous (sc) at recipient sites. IPsc raised to pressures below 50 mmHg and returned to baseline within 24 h. IPim raised above 50 mmHg and persisted CONCLUSION: F-PES appears associated to increased [TGC]p detectable at the SVC only. TGC micelle formation is thermodynamically adverse in plasma versus chyle, suggesting a preferential lymphatic uptake of grafted oil at the recipient site. This lymphatic uptake could be favored when graft oil is implanted im, where IP-im reach pressures that prevent venous drainage.

Thermosensitive hydrogel releasing nitric oxide donor and anti-CTLA-4 micelles for anti-tumor immunotherapy

Due to their autosynchronous roles in shaping the anti-tumor immune response, complex immune regulatory networks acting both locally within the tumor microenvironment as well as in its draining lymph nodes play critical roles in the cancer immunotherapy response. We describe herein a thermosensitive co-polymer hydrogel system formed from biocompatible polymers gelatin and Pluronic® F127 that are widely used in humans to enable the sustained release of a nitric oxide donor and antibody blocking immune checkpoint cytotoxic T-lymphocyte-associated protein-4 for efficient and durable anti-tumor immunotherapy. By virtue of its unique gel formation and degradation properties that sustain drug retention at the tumor tissue site for triggered release by the tumor microenvironment and formation of in situ micelles optimum in size for lymphatic uptake, this rationally designed thermosensitive hydrogel facilitates modulation of two orthogonal immune signaling networks relevant to the regulation of the anti-tumor immune response to improve local and abscopal effects of cancer immunotherapy.

Physicochemical Characterizations and Pharmacokinetic Evaluation of Pentazocine Solid Lipid Nanoparticles against Inflammatory Pain Model.

Pentazocine (PTZ), a narcotic-antagonist analgesic, has been extensively used in the treatment of initial carcinogenic or postoperative pain. Hepatic first-pass metabolism results in low oral bioavailability and high dose wastage. Herein, 10 mg (-)-Pentazocine (HPLC-grade) was incorporated to solid lipid nanoparticles (SLNs) using a double water-oil-water (w/o/w) emulsion by solvent emulsification–evaporation technique, followed by high shear homogenization to augment its oral bioavailability, considering the lymphatic uptake. The resulting SLNs were characterized for zeta potential (ZP), particle size (PS), and polydispersity index (PDI) using a zetasizer. The entrapment efficiency (EE) and loading capacity (LC) were calculated. Chemical interactions, through the identification of active functional groups, were assessed by Fourier-transformed infrared (FTIR) spectroscopy. The nature (crystallinity) of the SLNs was determined by X-ray diffractometry (XRD). The surface morphology was depicted by transmission electron microscopy (TEM). In vitro (in Caco-2 cells) and in vivo (in male Wistar rats) investigations were carried out to evaluate the PTZ release behavior and stability, as well as the cellular permeation, cytotoxicity, systemic pharmacokinetics, antinociceptive, anti-inflammatory, and antioxidative activities of PTZ-loaded SLNs, mainly compared to free PTZ (marketed conventional dosage form). The optimized PTZ-loaded SLN2 showed significantly higher in vitro cellular permeation and negligible cytotoxicity. The in vivo bioavailability and pharmacokinetics parameters (t1/2, Cmax) of the PTZ-loaded SLNs were also significantly improved, and the nociception and inflammation, following carrageenan-induced inflammatory pain, were markedly reduced. Concordantly, PTZ-loaded SLNs showed drastic reduction in the oxidative stress (e.g., malonaldehyde (MDA)) and proinflammatory cytokines (e.g., Interleukin (IL)-1β, -6, and TNF-α). The histological features of the paw tissue following, carrageenan-induced inflammation, were significantly improved. Taken together, the results demonstrated that PTZ-loaded SLNs can improve the bioavailability of PTZ by bypassing the hepatic metabolism via the lymphatic uptake, for controlled and sustained drug delivery.

Effects of lipid nanoparticles on physicochemical properties, cellular uptake, and lymphatic uptake of 6-methoxflavone

Effects of lipid nanoparticles on physicochemical properties, cellular uptake, and lymphatic uptake of 6-methoxflavone

Transport and lymphatic uptake of monoclonal antibodies after subcutaneous injection.

The subcutaneous injection has emerged to become a feasible self-administration practice for biotherapeutics due to the patient comfort and cost-effectiveness. However, the available knowledge about transport and absorption of these agents after subcutaneous injection is limited. Here, a mathematical framework to study the subcutaneous drug delivery of mAbs from injection to lymphatic uptake is presented. A three-dimensional poroelastic model is exploited to find the biomechanical response of the tissue by taking into account tissue deformation during the injection. The results show that including tissue deformability noticeably changes tissue poromechanical response due to the significant dependence of interstitial pressure on the tissue deformation. Moreover, the importance of the amount of lymph fluid at the injection site and the injection rate on the drug uptake to lymphatic capillaries is highlighted. Finally, variability of lymphatic uptake due to uncertainty in parameters including tissue poromechanical and lymphatic absorption parameters is evaluated. It is found that interstitial pressure due to injection is the major contributing factor in short-term lymphatic absorption, while the amount of lymph fluid at the site of injection determines the long-term absorption of the drug. Finally, it is shown that the lymphatic uptake results are consistent with experimental data available in the literature.

Hyaluronic acid carrier-based photodynamic therapy for head and neck squamous cell carcinoma

PurposeConventional photosensitizers for photodynamic therapy (PDT) typically have wide tissue distribution and poor water solubility. A hyaluronic acid (HA) polymeric nanoparticle with specific lymphatic uptake and highly water solubility was developed to deliver pyropheophorbide-a (PPa) for locally advanced head and neck squamous cell carcinoma (HNSCC) treatment. Methods and ResultsPPa was chemically conjugated to the HA polymeric nanoparticle via an adipic acid dihydrazide (ADH) linker. The conjugates were injected subcutaneously in a region near the tumor. Near-infrared (NIR) imaging was used to monitor distribution, and diode laser was used to activate PPa. The singlet oxygen generation efficiency of PPa was not affected by conjugation to HA nanoparticles at a PPa loading degree of 1.89 w.t.%. HA-ADH-PPa inhibited human HNSCC MDA-1986 cell growth only when photo-irradiation was applied. After HA-ADH-PPa treatment and radiation, NU/NU mice bearing human HNSCC MDA-1986 tumors showed reduced tumor growth and significantly enhanced survival time compared with an untreated group (p < 0.05). ConclusionsThese results demonstrate that HA-ADH-PPa could be useful for in vivo locoregional photodynamic therapy of HNSCC.

Multichromatic near-infrared imaging to assess interstitial lymphatic and venous uptake in vivo.

.Significance: Changes in interstitial fluid clearance are implicated in many diseases. Using near-infrared (NIR) imaging with properly sized tracers could enhance our understanding of how venous and lymphatic drainage are involved in disease progression or enhance drug delivery strategies.Aim: We investigated multichromatic NIR imaging with multiple tracers to assess in vivo microvascular clearance kinetics and pathways in different tissue spaces.Approach: We used a chemically inert IR Dye 800CW (D800) to target venous capillaries and a purified conjugate of IR dye 680RD with 40 kDa PEG (P40D680) to target lymphatic capillaries in vivo. Optical imaging settings were validated and tuned in vitro using tissue phantoms. We investigated multichromatic NIR imaging’s utility in two in vivo tissue beds: the mouse tail and rat knee joint. We then tested the ability of the approach to detect interstitial fluid perturbations due to exercise.Results: In an in vitro simulated tissue environment, free dye and PEG mixture allowed for simultaneous detection without interference. In the mouse tail, co-injected NIR tracers cleared from the interstitial space via distinct routes, suggestive of lymphatic and venous uptake mechanisms. In the rat knee, we determined that exercise after injection transiently increased lymphatic drainage as measured by lower normalized intensity immediately after exercise, whereas exercise pre-injection exhibited a transient delay in clearance from the joint.Conclusions: NIR imaging enables simultaneous imaging of lymphatic and venous-mediated fluid clearance with great sensitivity and can be used to measure temporal changes in clearance rates and pathways.

Solid nanostructured lipid carriers loaded with silymarin for oral delivery: Formulation development and evaluation

The present study was aimed at preparing stable dry adsorbed nanoparticles (DANs) of silymarin loaded nanostructured lipid carriers (NLCs). The prepared silymarin loaded NLCs and DANs were characterized for various quality parameters. Silymarin loaded NLCs were prepared by a modified hot melt emulsification ultra-sonication method using glyceryl monostearate (GMS), capmul MCM C8 EP (CAP) and gelucire 50/13 (G50/13) as solid lipid, liquid lipid and surfactant respectively. For better stability, NLC dispersion was converted into DANs by adsorbing them onto some suitable carriers. NLCs and DANs were characterized for particle size, polydispersity index, zeta potential, entrapment efficiency, drug loading, assay, thermal behavior, crystallinity and morphological study. The optimized NLCs have a mean particle size of 206.1±012.5 nm (size distribution of 0.249±0.058), a zeta potential of -32.5±1.2 mV with high entrapment of 95.60±0.45% and drug loading of 1.90±0.08%. The X-ray diffraction and endothermic peaks confirmed the maximum encapsulation of active in lipid matrices. The particles were spherical with smooth surface morphology. In-vitro release studies showed sustained drug release for up to 24 h. Ex-vivo permeation in the presence and absence of lymphatic blocker indicates the uptake of silymarin loaded NLCs by the lymphatic route. Silymarin loaded NLCs prepared had a nanosize distribution with high entrapment efficiency. The ex-vivo permeation study for optimized NLC formulation exhibited the lymphatic uptake of active. Dispersion stability was increased by preparing the DANs. The solid dry powder is used for oral reconstitution and can be further converted into tablets or filled into capsules.

Transport and Lymphatic Uptake of Biotherapeutics Through Subcutaneous Injection

Drug transport and uptake in the subcutaneous tissue receives increasing attention in biomechanical and pharmaceutical researches, as subcutaneous administration becomes a common approach for the delivery of biotherapeutics, such as monoclonal antibodies. In this paper, high-fidelity numerical simulations are used to investigate the mechanisms governing drug transport and absorption in the subcutaneous tissue, which is expressed as a porous medium modeled by Darcy’s law. The effects of tissue properties (permeability and porosity), the injection flow rate, and the vascular permeability of lymphatic vessels on the lymphatic uptake are studied. Additionally, an empirical formula for the lymphatic uptake during the injection is developed based on the numerical results. The roles of lymphatic drainage, blood perfusion, osmotic pressure, and the drug binding to the cells and the extracellular matrix in the lymphatic uptake are systematically studied. Furthermore, the drug distribution and absorption in a multi-layered porous medium are investigated to illustrate the effect of heterogeneity of permeability, as the permeability varies over a wide range in different layers of the tissue (such as dermis, subcutaneous tissue, muscle). While the interstitial pressure plays an essential role in the mechanisms regulating the absorption of free monoclonal antibodies, the binding and metabolism of drug proteins also affect the drug absorption by reducing the total free monoclonal antibodies.

Development, Testing, Parameterisation and Calibration of a Human PBPK Model for the Plasticiser, Di-(2-propylheptyl) Phthalate (DPHP) Using in Silico, in vitro and Human Biomonitoring Data.

A physiologically based pharmacokinetic model for Di-(2-propylheptyl) phthalate (DPHP) was developed to interpret the biokinetics in humans after single oral doses. The model was parameterized with in vitro and in silico derived parameters and uncertainty and sensitivity analysis was used during the model development process to assess structure, biological plausibility and behaviour prior to simulation and analysis of human biological monitoring data. To provide possible explanations for some of the counter-intuitive behaviour of the biological monitoring data the model included a simple lymphatic uptake process for DPHP and enterohepatic recirculation (EHR) for DPHP and the mono ester metabolite mono-(2-propylheptyl) phthalate (MPHP). The model was used to simultaneously simulate the concentration-time profiles of blood DPHP, MPHP and the urinary excretion of two metabolites, mono-(2-propyl-6-hydroxyheptyl) phthalate (OH-MPHP) and mono-(2-propyl-6-carboxyhexyl) phthalate (cx-MPHP). The availability of blood and urine measurements permitted a more robust qualitative and quantitative investigation of the importance of EHR and lymphatic uptake. Satisfactory prediction of blood DPHP and urinary metabolites was obtained whereas blood MPHP was less satisfactory. However, the delayed peak of DPHP concentration relative to MPHP in blood and second order metabolites in urine could be explained as a result of three processes: 1) DPHP entering the systemic circulation from the lymph, 2) rapid and very high protein binding and 3) the efficiency of the liver in removing DPHP absorbed via the hepatic route. The use of sensitivity analysis is considered important in the evaluation of uncertainty around in vitro and in silico derived parameters. By quantifying their impact on model output sufficient confidence in the use of a model should be afforded. This approach could expand the use of PBPK models since parameterization with in silico techniques allows for rapid model development. This in turn could assist in reducing the use of animals in toxicological evaluations by enhancing the utility of “read across” techniques.

Assessing Lymphatic Uptake of Lipids Using Magnetic Resonance Imaging: A Feasibility Study in Healthy Human Volunteers with Potential Application for Tracking Lymph Node Delivery of Drugs and Formulation Excipients.

Dietary lipids and some pharmaceutical lipid excipients can facilitate the targeted delivery of drugs to the intestinal lymphatics. Here, the feasibility of magnetic resonance imaging (MRI) for imaging lipid uptake into the intestinal lymphatics was assessed, shedding light on which lymph nodes can be targeted using this approach. Three healthy male volunteers were scanned at 3.0 T at baseline, 120, 180, 240, and 300 min post high-fat meal. A sagittal multi-slice image was acquired using a diffusion-weighted whole-body imaging sequence with background suppression (DWIBS) (pre inversion TI = 260 ms). Changes in area, major, and minor axis length were compared at each time point. Apparent diffusion coefficient (ADC) was calculated (b = 0 and 600 s/mm2) across eight slices. An average of 22 nodes could be visualised across all time points. ADC increased at 120 and 180 min compared to the baseline in all three participants by an average of 9.2% and 6.8%, respectively. In two participants, mean node area and major axis lengths increased at 120 and 180 min relative to the baseline. In conclusion, the method described shows potential for repeated lymph node measurements and the tracking of lipid uptake into the lymphatics. Further studies should focus on methodology optimisation in a larger cohort.

A Review on Novel vesicular systems for enhanced Oral bioavailability of Lipophilic drugs

The poor oral bioavailability of many drugs is mainly due to the poor aqueous solubility, chemical instability and pre-absorptive metabolism. Numerous approaches have been developed for enhancement of oral bioavailability and were currently in the clinical application. Even though, some drugs not meet the required clinical application due to the patient compliance and ineffective therapeutic levels. Vesicular delivery systems are considered as alternative delivery for the enhancement the bioavailability of this category of drugs. The enhanced bioavailability of the liphophilic drugs from the vesicular systems mainly due to the increased effective surface area of the drug in the presence of lipids, surfactants and co surfactants, enhanced lymphatic uptake, altered gastric motility and by virtue of their small particle size. Extensive literature is available for the properties, applications, and preparation and evaluation methods. This review mainly dealt with the reported drug loaded various vesicular systems such as liposomes, niosomes, lipid nanoparticles, self-emulsifying delivery system, nanosuspensions.

Is 18F-FDG PET/CT capable of differential diagnosis from tuberculous pleurisy from malignant mesothelioma?

18F-Fluorodeoxyglucose (FDG) PET/computerized tomography (CT) is a valuable method in the diagnosis of malignant pleural mesothelioma (MPM). But, some infections, particularly tuberculosis, are known to mimic cancer. We aimed to compare the FDG PET/CT findings of tuberculosis pleurisy (TP) and malignant mesothelioma and evaluate its role of differential diagnosis. We retrospectively reviewed the data from 85 patients (45 patients with MPM and 40 patients with TP) who underwent FDG PET/CT. All images were reevaluated and pleural thickening, maximum standardized uptake values (SUVmax), lymphatic uptake and accompanying parenchymal findings were noted. There was no significant difference in age and sex between the two groups. Pleural thickening was more prominent in the MPM group. Mean pleural thickness was 21.4 ± 18.6 mm in the MPM group and 6.8 ± 3.5 mm in the TP group (P = 0.0). Besides pleural pathology, lymph nodes involvement in the thoracic (P = 0.0) and extrathoracic area (P = 0.34) and parenchymal findings were prominent in the TP group (P = 0.0). However, there was no significant difference in pleural SUVmax values between the two groups (P = 0.61). Intense pleural FDG uptake can be observed in TP like malignant mesothelioma. For the evaluation of the pleural pathologies in the tuberculosis endemic countries, it should be considered that FDG PET/CT may have false-positive results. Evaluation of increased pleural FDG uptake together with the detected parenchymal findings and lymphatic involvement may help us to make more accurate interpretation of the diagnosis.