Effective Drug Transport Research Articles

One-Pot Synthesis and Characterization of Magnetic α-Fe2O3/CuO/CuFe2O4 Nanocomposite for Multifunctional Therapeutic Applications.

This study demonstrates a novel nanostructured drug delivery system utilizing α-Fe2O3/CuO/CuFe2O4 ternary nanocomposite for effective drug transport in sick tissues. Centella Asiatica plant extract was employed to synthesize the Fe2O3/CuO/CuFe2O4 nanocomposite via sol-gel auto combustion technique. The structural and morphological characteristics of the nanocomposite were investigated by XRD, FT-IR, SEM, EDX, and VSM for magnetic properties. The XRD analysis demonstrates the successful synthesis of Fe2O3/CuO/CuFe2O4 nanocomposite with an average crystallite size of 18.393 nm. The antioxidant and antifungal capabilities of this nanocomposite were assessed for its biological activity. A notable inhibitory zone was observed when tested against the Alternaria spp. and Bipolaris sorokiniana fungi. An IC50 value of 109.88 μg/ml was found in the DPPH test, indicating that the nanocomposite exhibited remarkable antioxidant characteristics. Subsequently, metronidazole was encapsulated with a success rate of 55.53 % at pH 1.2, while at pH 7.4 it gained 57.83 %. The drug release of nanocomposite at pH 1.2 after 330 min was 43.41 % and at pH 7.4 after 300 min it was 52.3 %. The results indicate its potential as an excellent candidate for drug delivery. Furthermore, pH was found to be an effective catalyst in the drug loading and release processes.

Nasal Delivery to the Brain: Harnessing Nanoparticles for Effective Drug Transport.

The nose-to-brain drug-delivery system has emerged as a promising strategy to overcome the challenges associated with conventional drug administration for central nervous system disorders. This emerging field is driven by the anatomical advantages of the nasal route, enabling the direct transport of drugs from the nasal cavity to the brain, thereby circumventing the blood-brain barrier. This review highlights the significance of the anatomical features of the nasal cavity, emphasizing its high permeability and rich blood supply that facilitate rapid drug absorption and onset of action, rendering it a promising domain for neurological therapeutics. Exploring recent developments and innovations in different nanocarriers such as liposomes, polymeric nanoparticles, solid lipid nanoparticles, dendrimers, micelles, nanoemulsions, nanosuspensions, carbon nanotubes, mesoporous silica nanoparticles, and nanogels unveils their diverse functions in improving drug-delivery efficiency and targeting specificity within this system. To minimize the potential risk of nanoparticle-induced toxicity in the nasal mucosa, this article also delves into the latest advancements in the formulation strategies commonly involving surface modifications, incorporating cutting-edge materials, the adjustment of particle properties, and the development of novel formulations to improve drug stability, release kinetics, and targeting specificity. These approaches aim to enhance drug absorption while minimizing adverse effects. These strategies hold the potential to catalyze the advancement of safer and more efficient nose-to-brain drug-delivery systems, consequently revolutionizing treatments for neurological disorders. This review provides a valuable resource for researchers, clinicians, and pharmaceutical-industry professionals seeking to advance the development of effective and safe therapies for central nervous system disorders.

Hydraulic conductivity of human cancer tissue: A hybrid study.

Elevated tumor tissue interstitial fluid pressure (IFP) is an adverse biomechanical biomarker that predicts poor therapy response and an aggressive phenotype. Advances in functional imaging have opened the prospect of measuring IFP non-invasively. Image-based estimation of the IFP requires knowledge of the tissue hydraulic conductivity (K), a measure for the ease of bulk flow through the interstitium. However, data on the magnitude of K in human cancer tissue are not available. We measured the hydraulic conductivity of tumor tissue using modified Ussing chambers in surgical resection specimens. The effect of the tumor microenvironment (TME) on K was investigated by quantifying the collagen content, cell density, and fibroblast density of the tested samples using quantitative immune histochemistry. Also, we developed a computational fluid dynamics (CFD) model to evaluate the role of K on interstitial fluid flow and drug transport in solid tumors. The results show that the hydraulic conductivity of human tumor tissues is very limited, ranging from approximately 10-15 to 10-14 m2/Pa∙s. Moreover, K values varied significantly between tumor types and between different samples from the same tumor. A significant inverse correlation was found between collagen fiber density and hydraulic conductivity values. However, no correlation was detected between K and cancer cell or fibroblast densities. The computational model demonstrated the impact of K on the interstitial fluid flow and the drug concentration profile: higher K values led to a lower IFP and deeper drug penetration. Human tumor tissue is characterized by a very limited hydraulic conductivity, representing a barrier to effective drug transport. The results of this study can inform the development of realistic computational models, facilitate non-invasive IFP estimation, and contribute to stromal targeting anticancer therapies.

Kidney targeting peptide-modified biomimetic nanoplatforms for treatment of acute kidney injury.

The management of acute kidney injury (AKI) imposes a significant medical burden. Due to the lack of effective drug transport vehicles, the administration of therapeutic agents for AKI cannot obtain the desired therapeutic effects. Kidney-targeted nanoparticles for renal delivery of drugs have shown promising potential as an emerging strategy for AKI therapy. However, these exogenous nanoparticles are rapidly cleared in the body and fail to achieve the expected renal targeting efficiency. Herein, we prepared the kidney targeting peptide-modified renal tubular epithelial cell membrane to coat zeolite imidazolate framework-8 nanoparticles for FGF21 delivery (KMZ@FGF21) for AKI treatment. KMZ@FGF21 could be efficiently internalized by renal cells and exhibited antioxidative, antiapoptotic and anti-inflammatory effects. A septic AKI murine model was established to assess the in vivo performance of KMZ@FGF21. The results showed that injected KMZ@FGF21 specifically accumulated in the injured kidney and exerted good renoprotective effects. This study provides an innovative thread for precise drug delivery in the treatment of various renal diseases.

Development of Polymeric Nanoparticles for Blood-Brain Barrier Transfer-Strategies and Challenges.

Neurological disorders such as Alzheimer's disease, stroke, and brain cancers are difficult to treat with current drugs as their delivery efficacy to the brain is severely hampered by the presence of the blood–brain barrier (BBB). Drug delivery systems have been extensively explored in recent decades aiming to circumvent this barrier. In particular, polymeric nanoparticles have shown enormous potentials owing to their unique properties, such as high tunability, ease of synthesis, and control over drug release profile. However, careful analysis of their performance in effective drug transport across the BBB should be performed using clinically relevant testing models. In this review, polymeric nanoparticle systems for drug delivery to the central nervous system are discussed with an emphasis on the effects of particle size, shape, and surface modifications on BBB penetration. Moreover, the authors critically analyze the current in vitro and in vivo models used to evaluate BBB penetration efficacy, including the latest developments in the BBB‐on‐a‐chip models. Finally, the challenges and future perspectives for the development of polymeric nanoparticles to combat neurological disorders are discussed.

Mucoadhesive Gelatin Buccal Films with Propranolol Hydrochloride: Evaluation of Mechanical, Mucoadhesive, and Biopharmaceutical Properties.

This study processes and characterizes propranolol hydrochloride/gelatin mucoadhesive buccal films. Two types of gelatin are used: Gelatin from porcine skin, type A (GA), and gelatin from bovine skin (GB). The influence of gelatin type on mechanical, mucoadhesive, and biopharmaceutical characteristics of buccal films is evaluated. Fourier-Transfer infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) analysis show that GA with propranolol hydrochloride (PRH) in the film (GAP) formed a physical mixture, whereas GB with PRH (GBP) form a compound-complex. Results of mechanical testing (tensile test, hardness) revealed that GAP films exhibit higher elastic modulus, tensile strength, and hardness. A mucoahesion test shows that GBP has higher adhesion strength, while GAP shows higher work of adhesion. Both in vitro release study and in silico simulation indicated that processed films can provide effective drug transport through the buccal mucosa. In silico simulation shows improved bioavailability from buccal films, in comparison to the immediate-release tablets—indicating that the therapeutic drug dose can be markedly reduced.

Modeling Nanocarrier Transport across a 3D In Vitro Human Blood-Brain-Barrier Microvasculature.

Polymer nanoparticles (NPs), due to their small size and surface functionalization potential have demonstrated effective drug transport across the blood-brain-barrier (BBB). Currently, the lack of in vitro BBB models that closely recapitulate complex human brain microenvironments contributes to high failure rates of neuropharmaceutical clinical trials. In this work, a previously established microfluidic 3D in vitro human BBB model, formed by the self-assembly of human-induced pluripotent stem cell-derived endothelial cells, primary brain pericytes, and astrocytes in triculture within a 3D fibrin hydrogel is exploited to quantify polymer NP permeability, as a function of size and surface chemistry. Microvasculature are perfused with commercially available 100-400 nm fluorescent polystyrene (PS) NPs, and newly synthesized 100 nm rhodamine-labeled polyurethane (PU) NPs. Confocal images are taken at different timepoints and computationally analyzed to quantify fluorescence intensity inside/outside the microvasculature, to determine NP spatial distribution and permeability in 3D. Results show similar permeability of PS and PU NPs, which increases after surface-functionalization with brain-associated ligand holo-transferrin. Compared to conventional transwell models, the method enables rapid analysis of NP permeability in a physiologically relevant human BBB set-up. Therefore, this work demonstrates a new methodology to preclinically assess NP ability to cross the human BBB.

Glutathione-adaptive peptide amphiphile vesicles rationally designed using positionable disulfide-bridges for effective drug transport

The drug loading/releasing capability of GSH-responsive nanovesicles self-assembled from peptide amphiphiles was controlled by varying the location and number of disulfide-linkages in the peptide for the selective drug-release into tumor cells.

The impact of gastrointestinal mucus on nanoparticle penetration – in vitro evaluation of mucus-penetrating nanoparticles for photodynamic therapy

Over the last years nanoparticles (NP) have become a promising vehicle as drug delivery systems for photodynamic therapy (PDT), combining the advantages of an effective drug transport to the target cells and the reduction of undesired side effects. The in vitro evaluation of new nanoparticulate formulations has become a rising problem since cell culture models differ from the in vivo situation of the human body to a large extent. Particularly, in case of gastrointestinal tumors, after peroral application nanoparticles are challenged by overcoming the mucus layer as a first physical barrier before reaching the target cells, an aspect often neglected in literature. However, the presence of mucus is crucial for in vitro models to evaluate mucus-penetrating potential of surface-modified nanoparticulate drug carrier systems. Biodegradable poly(dl-lactide-co-glycolide) (PLGA) NP loaded with the model photosensitizer 5,10,15,20-tetrakis(m-hydroxyphenyl)porphyrin (mTHPP) were surface modified with either poly(ethylene glycol) (PEG) or chitosan (CS) to gain mucus-penetrating or mucoadhesive particle properties. All NP systems were compared to each other and to free mTHPP regarding cytotoxicity and cellular uptake in HT-29 cells and mucus producing HT-29-MTX cells. For PEGylated mTHPP-PLGA-PEG-NP a significantly higher accumulation was obtained in HT-29-MTX cells compared to all other tested nanoparticles and the free drug. Additionally, a mucus-containing Transwell® model, consisting of HT-29-MTX cells, confirmed these results, representing a promising in vitro screening method for mucus-penetrating particle properties.

Folate-directed zinc (II) phthalocyanine loaded polymeric micelles engineered to generate reactive oxygen species for efficacious photodynamic therapy of cancer.

Targeted and effective drug transport is becoming an attractive option in cancer therapy since it can improve drug efficacy and reduce drugs' side effects in normal tissues. In addition to using specific surface ligand molecules, the selective drug delivery can be accomplished via enhanced permeability and retention effect. Therefore, in our studies, we entrapped zinc (II) phthalocyanine (ZnPc) - a second generation photosensitizer - in folate-functionalized micelles of the biocompatible, FDA-approved for biomedical application diblock copolymer methoxypoly(ethylene oxide)-b-poly(L-lactide) (mPEG-b-PLLA) and its derivative with folate (FA) attached to the end of PEG chain (FA-PEG-b-PLLA). Dynamic light scattering (DLS) measurements confirmed the micellar size to be <150 nm in diameter, a low polydispersity index, and good colloid stability of the studied nanocarriers, while atomic force microscopy (AFM) was used to study their morphology. The application potential of the resulting micelles was evaluated in cyto- and photocytotoxicity studies in conjunction with intracellular distribution and accumulation imaging of the photosensitizer delivered to ovarian carcinoma (SKOV-3) and metastatic melanoma (Me45) cell lines. Reactive oxygen species generation study was performed after photodynamic reaction, and cellular cytoskeleton reorganization was visualized after undergoing a photodynamic reaction. The results demonstrated that the functionalized polymeric micelles are promising nanocarriers for photodynamic therapy procedures and can be used in anticancer drug delivery.

Rational design of nanosystems for simultaneous drug delivery and photodynamic therapy by quantum mechanical modeling.

Drug delivery systems are based on reversible interactions between carriers and drugs. Spacers are often introduced to tailor the type of interaction and to keep drugs intact. Here, we model a drug delivery system based on a functionalized curved TiO2 nanoparticle of realistic size (700 atoms - 2.2 nm) by the neurotransmitter dopamine to carry the anticancer chemotherapeutic agent doxorubicin (DOX). The multiscale quantum chemical study aims at unraveling the nature and mechanism of the interactions between the components and the electronic properties of the composite system. We simulate the temperature effect through molecular dynamics runs of thermal annealing. Dopamine binds preferentially to low coordinated Ti sites on the nanoparticle through dissociated bidentate and chelate modes involving the diol groups. DOX is tethered by H-bonds, π-π stacking, dipole-dipole interactions and dispersion forces. Comparing different coverage densities of the spacer on the nanoparticle surface, we assess the best conditions for an effective drug transport and release: only at full coverage, DOX does not slip among the dopamine molecules to reach the nanoparticle surface, which is crucial to avoid the formation of stable coordinative bonds with under-coordinated Ti atoms. Finally, given the strong absorption properties and fluorescence of DOX and of the TiO2 photocatalyst, we model the effect of light irradiation through excited state calculations to localize excitons and to follow the charge carrier's life path. This fundamental study on the nature and mechanism of drug/carrier interaction provides a solid ground for the rational design of new experimental protocols for a more efficient drug transport and release and its combination with photodynamic therapy.

Efficacy and Safety of Noninvasive Intravesical Instillation of Onabotulinum Toxin-A for Overactive Bladder and Interstitial Cystitis/Bladder Pain Syndrome: Systematic Review and Meta-analysis

ObjectiveTo investigate the efficacy and safety of noninvasive intravesical instillation of onabotulinum toxin-A (OBTX-A) through systematic review and meta-analysis. Recently, several studies of noninvasive intravesical instillation of OBTX-A have been published. However, its efficacy is not well validated yet compared to well-known efficacy of minimally invasive intravesical injection of OBTX-A. MethodSystematic review and meta-analysis were performed to evaluate the efficacy of noninvasive intravesical instillation of OBTX-A in patients with overactive bladder and interstitial cystitis/bladder pain syndrome by measuring outcomes such as urgency episode per 72 hours, frequency per 72 hours, urgency urinary incontinence, voided volume (VV), postvoided residual volume, maximum flow rate, and patient perception of bladder condition. ResultSix trials in 4 studies that compared instillation of OBTX-A and placebo involving 248 patients (121 experimental and 127 controls) were included for final data extraction. Instillation of OBTX-A significantly increased VV, with a mean difference of 38.48 (95% confidence interval: 76.05, 0.92) compared to the placebo group. However, other outcomes showed statistically insignificant changes. Major adverse events were not reported in the group receiving intravesical instillation of OBTX-A. ConclusionIntravesical instillation of OBTX-A showed limited efficacy with improvement of VV for treatment of overactive bladder or interstitial cystitis/bladder pain syndrome. More studies are needed to overcome the efficacy of current noninvasive bladder instillation of OBTX-A regarding effective drug transport.

Lenghty reverse poly(butylene oxide)-poly(ethylene oxide)-poly(butylene oxide) polymeric micelles and gels for sustained release of antifungal drugs

In this work, we present a detailed study of the potential application of polymeric micelles and gels of four different reverse triblock poly(butylene oxide)–poly(ethylene oxide)–poly(butylene oxide) copolymers (BOnEOmBOn, where n denotes the respective block lengths), specifically BO8EO90BO8, BO14EO378BO14, BO20EO411BO20 and BO21EO385BO21, as effective drug transport nanocarriers. In particular, we tested the use of this kind of polymeric nanostructures as reservoirs for the sustained delivery of the antifungals griseofulvin and fluconazole for oral and topical administration. Polymeric micelles and gels formed by these copolymers were shown to solubilize important amounts of these two drugs and to have a good stability in physiologically relevant conditions for oral or topical administration. These polymeric micellar nanocarriers were able to release drugs in a sustained manner, being the release rate slower as the copolymer chain hydrophobicity increased. Different sustained drug release profiles were observed depending on the medium conditions. Gel nanocarriers were shown to display longer sustained release rates than micellar formulations, with the existence of a pulsatile-like release mode under certain solution conditions as a result of their inner network structure. Certain bioadhesive properties were observed for the polymeric physical gels, being moderately tuned by the length and hydrophobicity of the polymeric chains. Furthermore, polymeric gels and micelles showed activity against the yeast Candida albicans and the mould demartophytes (Trichophyton rubrum and Microsporum canis) and, thus, may be useful for the treatment of different cutaneous fungal infections.

Revisiting bone targeting potential of novel hydroxyapatite based surface modified PLGA nanoparticles of risedronate: Pharmacokinetic and biochemical assessment

Hydroxyapatite based biodegradable mPEG-PLGA nanoparticles of risedronate (mPEG-PLGA-RIS-HA) were prepared by water miscible dialysis method for synergistic treatment of osteoporosis. The bone targeting potential of prepared nanoparticles was evaluated by performing the cell viability study and protein estimation in pre-osteoblast cell line (MC3T3E1). Biochemical and in-vivo pharmacokinetic studies on osteoporotic rat model treated with different formulations were performed. Under the biochemical study ALP, TRAP, HxP and Calcium levels were determined. Osteoporotic model treated with prepared nanoparticles indicated significant effect on bone. Pharmacokinetic studies revealed 6-fold and 4-fold increase in the relative bioavailability after intravenous and oral administration of nanoparticles respectively as compared to marketed formulation confirming better effective drug transport. Biochemical investigations also showed a significant change in biomarker level which ultimately lead to bone formation/resorption. A stability analysis has also been carried out according to ICH guidelines (Q1AR2) and shelf life was found to be 1year and 4 months for the prepared formulation. Thus the results of present studies indicated that mPEG-PLGA-RIS-HA NPs has a great potential for sustained delivery of RIS for the treatment and prevention of osteoporosis and to minimize the adverse effects of RIS typically induced by its oral administration.

Three Ply-Walled Microcapsules for Enhanced Pharmacokinetics of Poorly Absorbed Risedronate Sodium: Novel Stratagem Toward Osteoporosis

Effective and optimized drug delivery has always been one of the major challenge for the researchers in the last few decades and is still a very active field of research. The present investigation focuses on the development of a novel strategy to enhance the bioavailability of risedronate sodium which shows very poor and erratic absorption. A multiple emulsion technique has been used to prepare the three ply-walled microcapsules needed for targeting the specific sites. Box-Behnken model has been selected to optimize the effect of various process variables on particle size and entrapment efficiency. Optimized microcapsules (PN-F) were found to have a particle size of 3.97 ± 0.29 μm (PDI = 0.19 ± 0.09), entrapment efficiency of 79.12 ± 2.19 %, and maximum release of 96.34 ± 3.426 and 97.32 ± 2.486 % in simulated gastric and intestinal fluid, respectively, over the period of 24 h. In vivo pharmacokinetic study exhibits a substantial increase in the absolute bioavailability of the microcapsules (F = 40.68 ± 2.636 %) as compared to marketed formulation, RISOFOS®, CIPLA (F = 0.98 ± 0.086 %) (p < 0.01) leading to a more effective drug transport. A stability analysis has also been carried out and is found to be quite promising for the present formulation. The obtained outcomes strongly support the fact that the present formulation not only plays a vital role in the optimized delivery of risedronate sodium in osteoporosis management but also depicts negligible pitfalls.

The photodynamic effect of far-red range phthalocyanines (AlPc and Pc green) supported by electropermeabilization in human gastric adenocarcinoma cells of sensitive and resistant type

IntroductionElectroporation (EP) is commonly applied for effective drug transport thorough cell membranes based on the application of electromagnetic field. When applied with cytostatics, it is called electrochemotherapy (ECT) – a quite new method of cancer treatment. A high-voltage pulse causes the formation of temporary pores in the cell membrane which create an additional way for the intracellular drug transport. In the current work, EP was effectively merged with the already known photodynamic therapy (PDT) to selective photosensitizers’ delivery to diseased tissue. The application of electroporation can reduce the dose of applied drug. Research objectiveThe aim of research was to evaluate the effectiveness of photodynamic reaction using two near infrared cyanines (AlPc and Pc green) combined with electroporation in two human gastric adenocarcinoma cell lines. Materials and methodsTwo human cell lines – EPG85-257P (parental) and EPG85-257RDB (resistant to daunorubicin) – of gastric cancer were used. The effect of two photosensitizers (aluminum 1,8,15,22-tetrakis(-phenylthio)-29H,31H-phthalocyanine chloride and Phthalocyanine green) was investigated. The efficiency of EP parameters was assessed by propidium iodide uptake. The viability assay was applied to analyse EP, PDT and EP-PDT effect. Cyanine localization was determined by confocal microscopy. Immunocytochemical evaluation of manganese superoxide dismutase and glutathione S-transferase-pi was determined after applied therapies. ResultsPDT in combination with EP affected the viability of EPG85-257P and EPG85-257RDB cells negatively while both cyanine were used. The most evident changes were observed in the following concentrations: 15, 10 and 5μM. The optimal field strength for enhanced EP-PDT was 800 and 1200V/cm. AlPc distributed selectively in the lysosomes of parental cell line. ConclusionsPDT, enhanced by EP, caused decreased viability when compared to the application of PDT alone. Both phthalocyanines found to be more effective after electroporation. Due to the low concentration of light-sensitive compounds and safety of electroporation itself, a treatment plan can be an alternative therapeutic modality against gastric adenocarcinomas.

Brain delivery of valproic acid via intranasal administration of nanostructured lipid carriers: in vivo pharmacodynamic studies using rat electroshock model

The treatment of brain disorders is one of the greatest challenges in drug delivery because of a variety of main barriers in effective drug transport and maintaining therapeutic concentrations in the brain for a prolonged period. The objective of this study was delivery of valproic acid (VPA) to the brain by intranasal route. For this purpose, nanostructured lipid carriers (NLCs) were prepared by solvent diffusion method followed by ultrasonication and characterized for size, zeta potential, drug-loading percentage, and release. Six groups of rats each containing six animals received drug-loaded NLCs intraperitoneally (IP) or intranasally. Brain responses were then examined by using maximal electroshock (MES). The hind limb tonic extension:flexion inhibition ratio was measured at 15-, 30-, 60-, 90-, and 120-minute intervals. The drug concentration was also measured in plasma and brain at the most protective point using gas chromatography method. The particle size of NLCs was 154 ± 16 nm with drug-loading percentage of 47% ± 0.8% and drug release of 75% ± 1.9% after 21 days. In vivo results showed that there was a significant difference between protective effects of NLCs of VPA and control group 15, 30, 60, and 90 minutes after treatment via intranasal route (P < 0.05). Similar protective effect was observed in rats treated with NLCs of VPA in intranasal route and positive control in IP route (P > 0.05). Results of drug determination in brain and plasma showed that brain:plasma concentration ratio was much higher after intranasal administration of NLCs of VPA than the positive control group (IP route). In conclusion, intranasal administration of NLCs of VPA provided a better protection against MES seizure.

Supramolecularassemblies for the active drug targeting to the brain

This review focuses on targeted drug delivery using supramolecular assemblies for the treatment of cerebral diseases. To enable effective drug transport, colloidal systems have to both evade the reticuloendothelial system and circumvent the drug efflux mechanism. Additionally, they have to accumulate in high concentrations in desired sites, thus increasing the therapeutic index of drugs and reducing potential toxic side effects. In order to enhance their therapeutic efficiency, nanocarriers have been conjugated to biomolecules recognizing specific or up-regulated receptors and antigens located on the membrane of targeted cells. This strategy known as active targeting showed promising results for both targeting and transport across physiological barriers such as the blood brain barrier.

Understanding the role of the tumour vasculature in the transport of drugs to solid cancer tumours

The vasculature of tumours imposes certain barriers that transport of anti-cancer drugs must overcome. Here follows an account of development of a general computational model that describes the mechanisms of drug transport to a solid tumour, with an emphasis on modelling the vasculature using solute transport concepts. Investigation into the biological parameters that enhance/prevent anticancer drug transport to the tumour provides a means to evaluate the effects of these parameters on the treatment process. Sensitivity analysis of these provides useful insights concerning anticancer drug transport mechanisms from the vasculature to the solid tumour for a non-specified drug and non-specified solid tumour by revealing the conditions that promote or prevent effective drug transport. The effect of the vasculature on transport efficiency is studied using a parametric analysis of some of the transport and biological parameters. Understanding the various transport mechanisms provides a basis to evaluate the effectiveness of the drug treatment a priori. It was found that increases in the capillary hydrostatic pressure, diffusive permeability coefficient and hydraulic conductivity all result in a decrease in tumour size. Similarly, decreases in the interstitium hydrostatic pressure and filtration constant result in a decrease in tumour size. Dependence of the change in the tumour size to changes in these parameters is non-linear. These results demonstrate the potential of the integrated computational model of the tumour and its vasculature to estimate efficacy of a particular treatment process. Regardless of the dependency of the outcome on the assumed model parameters and the assumed kinetics, mathematical models of this type can provide more explanation on the issues related to the transport barriers, the efficacy of the treatment, and the development of effective anticancer drugs. A case study also is presented to demonstrate the model's flexibility to accommodate a two-cell-glioma population.

Intranasal mucoadhesive microemulsions of zolmitriptan: Preliminary studies on brain-targeting

The aim of this investigation was to prepare microemulsions containing zolmitriptan (ZT) for rapid drug delivery to the brain to treat acute attacks of migraine and to characterize microemulsions and evaluate biodistribution in rats. Zolmitriptan microemulsions (ZME) were prepared using the titration method and were characterized for globule size distribution and zeta potential. ZT was radiolabeled using 99mTc (technetium) and radiolabeled-drug formulations of ZT were used to carry out biodistribution of drug in the brain of Swiss albino rats after intranasal and intravenous administration. The pharmacokinetic parameters, drug targeting efficiency (%DTE) and direct nose-to-brain drug transport (%DTP) were calculated. Brain scintigraphy imaging in rats were also performed to ascertain the uptake of drug into the brain. ZME were transparent and stable with mean globule size of 35 ± 25 nm and zeta potential of − 38– − 52 mV. 99mTc-labeled-drug formulations of ZT were found to be stable and suitable to perform in vivo studies. Following intranasal administrations of zolmitriptan mucoadhesive microemulsion (ZMME), ZME, Zolmitriptan solution (ZS) and intravenous administration of ZS, brain/blood uptake ratios at 0.50 h were found to be 0.70, 0.56, 0.27 and 0.13, respectively, indicating effective brain-targeting following intranasal administration of ZMME. Comparing intranasal administration of ZMME with intravenous administration of ZME, the %DTE and %DTP were found higher indicating effective drug transport following intranasal administration and highest brain-targeting following ZMME administration. Rat brain scintigrams showed substantial uptake of drug into the brain after intranasal administration of ZMME. Studies of this investigation conclusively demonstrated rapid and larger extent of transport into the rat brain following intranasal administration of ZMME and can play a promising role in the treatment of acute attacks of migraine.