Direct Drug Targeting Research Articles

A Feasibility Study of In Vivo Control and Tracking of Microrobot Using Taxicab Geometry for Direct Drug Targeting.

In vivo direct drug targeting aims at delivering drug molecules loaded on microrobots to the diseased site using the shortest possible physiological routes, which potentially improves targeting efficiency and reduces systemic toxicity. It is thus essential to consider realistic in-body limitations for direct drug targeting applications. Here, we present a novel controller for microrobot maneuver by considering four key in vivo constraints: non-Euclidean structure of capillaries, irreversibility of blood flow, invisibility of microvasculature, and inaccuracy of microrobot tracking. We use the taxicab geometry of capillaries as the a priori knowledge for steering and tracking a microrobot in lattice-like vessels. Furthermore, we introduce a minimax repulsive boundary function to prevent the microrobot from getting too close to the boundaries imposed by the direction of blood flow. We also propose a novel Kalman filtering algorithm to reduce tracking error, while avoiding possible obstacles such as vessel walls without knowing their actual locations. The proposed control method consists of four modules, namely a model predictive control module for tumor targeting, a Kalman filtering module for microrobot tracking, a blind obstacle detection module, and a vessel structure estimation module. The interplay of these four modules offers successful maneuver and tracking of the microrobot while avoiding obstacles in a blind manner by utilizing the taxicab geometry of blood vessels. We present a comprehensive in silico simulation study to verify our designed controller.

Brain targeted delivery of sumatriptan succinate loaded chitosan nanoparticles: Preparation, In vitro characterization, and (Neuro-)pharmacokinetic evaluations

Migraine is a neurovascular disorder characterized by nausea, vomiting, pain, photophobia, phonophobia, and in some cases auras. Because of the complexity of the pathophysiology of migraine and the limited systemic availability of sumatriptan succinate after oral administration, oral delivery of sumatriptan succinate encountered with important limitations. During this study formulation and evaluation of the neuropharmacokinetics of intravenous and intranasal (IN)-administered sumatriptan succinate-loaded chitosan nanoparticles were considered. At first, formulation and characterization of drug-loaded chitosan nanoparticles were performed and then neuropharmacokinetic parameters including direct transport percentage (DTP) and drug targeting efficiency (DTE) were assessed by performing an in vivo study on rats. Ionic gelation technique led to the preparation of nanoparticles with 105 nm mean diameter and polydispersity index (PDI) of 0.38. The drug entrapment efficiency (EE) for the nanoparticles was calculated 59.60 ± 2.12%. In vitro release study indicated that 12 and 32% of the drug were released in the first 1 and 4 h after the beginning of the experiment. DTE and DTP of IN-administered nanoparticles were calculated 493.39% and 79.79%, respectively. Neuropharmacokinetic evaluations of the polymeric nanoparticles represent a suitable brain delivery system. The high DTP value for nanoparticles confirms the satisfactory entrance of the drug into the higher parts of the brain.

Single Residue Variation in Skeletal Muscle Myosin Enables Direct and Selective Drug Targeting for Spasticity and Muscle Stiffness

Muscle spasticity after nervous system injuries and painful low back spasm affect more than 10% of global population. Current medications are of limited efficacy and cause neurological and cardiovascular side effects because they target upstream regulators of muscle contraction. Direct myosin inhibition could provide optimal muscle relaxation; however, targeting skeletal myosin is particularly challenging because of its similarity to the cardiac isoform. We identified a key residue difference between these myosin isoforms, located in the communication center of the functional regions, which allowed us to design a selective inhibitor, MPH-220. Mutagenic analysis and the atomic structure of MPH-220-bound skeletal muscle myosin confirmed the mechanism of specificity. Targeting skeletal muscle myosin by MPH-220 enabled muscle relaxation, in human and model systems, without cardiovascular side effects and improved spastic gait disorders after brain injury in a disease model. MPH-220 provides a potential nervous-system-independent option to treat spasticity and muscle stiffness.

Nose-to-Brain Delivery of Diazepam from an Intranasal Aqua-Triggered In-Situ (ATIS) Gelling Microemulsion: Monitoring Brain Uptake by Microdialysis.

An innovative intranasal aqua-triggered in-situ (ATIS) gel is a polymer-free in-situ gelling microemulsion which gels instantaneously on contact with minute quantities of water to form a mucoadhesive gel. The objective of the study was to develop ATIS diazepam (ATIS-diazepam) as an alternative to the injection for epileptic emergencies and evaluate its brain uptake and nose-to-brain targeting efficiency in rats. ATIS-diazepam (1mg/100 µL) was prepared and characterized for in vitro formulation characteristics. An LC-MS/MS method was developed and validated for the bioanalysis of diazepam. In vivo studies for pharmacokinetics, brain uptake and nasal irritation of intranasal ATIS-diazepam were conducted in rats. Brain uptake was investigated with brain microdialysis, a highly sensitive technique enabling quantification of free drug, which correlates to efficacy. ATIS-diazepam exhibited globule size < 200nm, low viscosity, negative zeta potential and good stability. A significant increase in mucoadhesion was exhibited by ATIS-diazepam following the addition of a small quantity of water. ATIS-diazepam showed burst release in pH 6.4 with 50% diazepam release in ~ 10min, which was sustained over 1h. The absolute bioavailability was ~ 50% with both intranasal free-diazepam and ATIS-diazepam. Intranasal administration of ATIS-diazepam revealed immediate absorption with rapid and high brain extracellular fluid concentration compared to intravenous free-diazepam solution. The estimated direct transport potential and drug targeting efficiency of intranasal ATIS-diazepam was significantly higher (2-fold) than intranasal free-diazepam solution, which was attributed to the mucoadhesive and microemulsion properties of ATIS-diazepam. The nasal irritation study revealed the safety of ATIS-diazepam compared to free-diazepam solution. Intranasal ATIS-diazepam showed promise of higher direct nose-to-brain targeting, better safety and hence has an immense implication in the treatment of epileptic emergencies.

Blind Obstacle Avoidance Using Taxicab Geometry for NanorobotAssisted Direct Drug Targeting.

In this paper, we present a novel controller for steering nanorobots in lattice-like vessel systems while avoiding potential obstacles such as the vessel walls without any prior knowledge of the obstacles' positions. The proposed control method consists of two sub-modules, namely a blind obstacle avoidance (BOA) and a model predictive control (MPC). In the case that a nanorobot might encounter an obstacle on its path, the BOA module is activated, which gives rise to a desirable heading angle to change the direction of the nanorobot's movement to bypass the obstacle. On the other hand, the MPC module offers a series of actuating field's directions that control the nanorobots' movement in the blood vessel with a grid structure representing potential paths of vascular growth, and introduces a repulsive boundary function to stop nanorobots from getting too close to the boundaries. This new formulation offers successful control and steering of nanorobots while avoiding obstacles in a blind manner by taking into account realistic in vivo physical constraints. Simulation results demonstrate the effectiveness of the proposed feedback control design.

An Efficient and Cost-Effective Nose-Only Inhalational Chamber for Rodents: Design, Optimization and Validation.

The mainstay treatment of pulmonary disorders lies around the direct drug targeting to the lungs using a nebulizer, metered-dose inhaler, or dry powder inhaler. Only few inhalers are available in the market that could be used for inhalational drug delivery in rodents. However, the available rodent inhalers invariably require high cost and maintenance, which limits their use at laboratory scale. The present work, therefore, was undertaken to develop a simple, reliable, and cost-effective nose-only inhalation chamber with holding capacity of three mice at a time. The nebulized air passes directly and continuously from the central chamber to mouthpiece and maintains an aerosol cloud for rodents to inhale. Laser diffraction analysis indicated volume mean diameter of 4.02 ± 0.30μm, and the next-generation impactor studies, however, revealed mean mass aerodynamic diameter of 3.40 ± 0.27μm, respectively. An amount of 2.05 ± 0.20mg of voriconazole (VRC) was available for inhalation at each delivery port of the inhaler. In vivo studies indicated the deposition of 76.12 ± 19.50μg of VRC in the mice lungs when nebulized for a period of 20min. Overall, the developed nose-only inhalation chamber offers a reliable means of generating aerosols and successfully exposing mice to nebulization.

Overcoming Channel Uncertainties in Touchable Molecular Communication for Direct-Drug-Targeting-Assisted Immuno-Chemotherapy.

The performance of targeted immuno-chemotherapy of tumor is highly exposed to drug absorption in systemic circulation, which reduces its efficiency and increases side-effects. Direct drug targeting (DDT) combined with immuno-chemotherapy has the potential to mitigate the undesired systemic exposure, by using drug-loaded nanorobots to target cancer cells with the shortest possible physiological routes. This process can be modeled by the "touchable" (i.e., externally controllable and trackable) molecular communication system. However, such a complex process still suffers from various pharmacokinetic uncertainties caused by diffusion, degeneration, and branching of nanorobots (DDT pharmacokinetic uncertainties), as well as tumor/immune system modeling errors. The current work aims at identifying optimal drug administration plans by overcoming such challenges. A revisited tumor-immune interaction model is proposed to incorporate randomness of the drug concentration in the tumor site. Then, a robust multiple model predictive control (MMPC) scheme for the proposed tumor-immune interaction model is designed that uses multiple system models and an adaptive switch to identify the optimal plans for mixed drug administration via drug-loaded nanorobots. Furthermore, a wide range of prediction horizons under different loss scenarios of drug-loaded nanorobots and system model mismatches have been investigated in order to identify safe operating regions. From the molecular communications paradigm, this can be considered as a more robust information transmission system with feedback of channel state information to the transmitter implemented in the control unit. The efficacy of the proposed MMPC is illustrated through identification of globally optimized drug administration schedules subject to various controller operation imperfections, which lead to successful cancer treatment as demonstrated through computational experiments. By combining DDT with conventional mixed immunotherapy and chemotherapy, the proposed robust MMPC offers promising performance in controlling tumor growth while keeping the immune cell density higher than a specific level in the presence of both DDT pharmacokinetic uncertainties and system model mismatches. We believe that the proposed design framework represents an important first step towards clinically relevant DDT in the combined immunotherapy and chemotherapy of tumor given its robust performance.

Latticed Channel Model of Touchable Communication Over Capillary Microcirculation Network.

Recent progress on bioresorbable and bio-compatible miniature systems provides prospects for developing novel nanorobots operating inside the human body. These nanoscale systems are expected to dissolve in vivo and cause no side effect after completing their tasks. Motivated by these advancements, we have developed the analytical framework of touchable molecular communication (TouchCom) to describe the process of direct drug targeting (DDT) using externally controllable nanorobots. Built upon our previous work, we develop a novel latticed channel model of TouchCom for an interconnected capillary network near a targeted tumor area. Specifically, we propose a two-dimensional grid to synthesize the microcirculation environment, which is used to describe the propagation process of nanorobots. Furthermore, by applying the concept of multiple-input multiple-output (MIMO) systems in wireless communications to the therapeutic window in cancer treatment, we propose a MIMO DDT strategy in the latticed channel to enhance the targeting efficiency while minimizing the adverse effect of drug toxicity. Based on the proposed model, we study the influence of blood flow direction on the efficiency of DDT, and introduce a compensation strategy with the help of an external guiding field to mitigate the misalignment between the direction of blood flow and the tumor location.

Direct Drug Targeting into Intracellular Compartments: Issues, Limitations, and Future Outlook.

Intracellular compartment drug delivery is a promising strategy for the treatment of diseases. By this way, medicines can delivered to particular intracellular compartments. This maximizes the therapeutic efficacy and safety of medicines, particularly of anticancer and antiviral drugs. Intracellular compartment drug delivery is either indirectly by targeting of cell nucleus as central compartment of the cell or directly through the targeting of compartments itself. Drugs or nanoshuttles labeled with compartment's localization signal represent a smart tactic for subcellular compartment targeting. There are several boundaries prevent the arrival of shuttles to the specified intracellular compartments. These boundaries include selective permeability of biomembranes, efflux transporters, and lysosomes. The utilization of specific ligands during design of drug delivery nanoshuttles permits the targeting of specified intracellular compartment. Therefore drugs targeting could correct the diseases associated organelles. This review highlights the direct targeting of the medicines into subcellular compartment as a promising therapeutic strategy.

Overcoming Channel Uncertainties in Molecular-Communication-Inspired Direct Drug Targeting.

Recent progress in the development of new methods for cancer treatment has shown advantages of multiple therapies over mono-therapy. In particular, direct drug targeting (DDT) combined with mixed immunotherapy and chemotherapy has the potential to mitigate the undesired side-effects allied with conventional therapies, where nanorobots in DDT carry therapeutic agents through the blood vessel channel in order to localize and target diseased tissue with a safe drug interaction. This process can be modeled by a "touchable" (i.e., externally controllable and trackable) molecular communication (MC) system. However, in such a complex process overcoming unavoidable vascular channel uncertainties remains a great challenge. In this paper a multiple model predictive controller (MMPC) is proposed, which is robust against random channel uncertainties. The efficacy of the proposed method is illustrated through identification of globally optimized drug administration schedules. Furthermore, we introduce upper and lower bounds on the inputs and outputs which lead to clinically realistic constraints on the system. Simulation results demonstrate the promising performance of proposed MMPC to control tumor growth in presence of vascular channel uncertainties in MC-inspired DDT for cancer treatment.

Nanoemulsions for "Nose-to-Brain" Drug Delivery.

The blood–brain barrier (BBB) plays a fundamental role in protecting the brain from toxic substances and therefore also controls and restricts the entry of therapeutic agents. The nasal administration of drugs using the nose-to-brain pathway allows direct drug targeting into the brain, avoiding the first-pass effect and bypassing the BBB. Through the nasal route, the drug can access the brain directly along the trigeminal and olfactory nerves, which are located in the upper part of the nasal cavity. Nanoemulsions are formulations belonging to the field of nanomedicine. They consist of emulsions (commonly oil in water) stabilized by one or more surfactants—and eventually co-surfactants—delivered in droplets of small dimensions (sizes of 100–300 nm or less) with a high surface area. A mucoadhesive polymer such as chitosan can be added to the formulation to impair rapid nasal clearance. Nanoemulsions represent promising formulations to deliver drugs directly into the brain through the intranasal route. Therefore, they can be used as a possible alternative to oral administration, avoiding problems such as low solubility in water, poor bioavailability, enzymatic degradation and slow onset of action. This review focuses the present situation in literature regarding the use of nanoemulsions for nose-to-brain targeting, with particular attention to recent publications. Nasal nanoemulsions appear to be effective, non-invasive and safe drug delivery systems to achieve brain targeting for the treatment of neurological diseases.

Biocompatible Fe3O4/chitosan scaffolds with high magnetism.

Durable and biocompatible magnetic scaffolds prepared by simple approaches are important for the development of tissue engineering. In this work, by freeze-drying method and without using any crosslinker, we successfully fabricated Fe3O4/chitosan magnetic scaffolds that belong to hard magnetic materials and are stable in physiological fluid. In vitro biocompatibility assay showed that mouse mesenchymal progenitor cells grow normally on the surface of the scaffolds. So these magnetic scaffolds have potentials to be used in tissue engineering as implants that independently direct drug targeting.

Ion channelopathies in functional GI disorders.

In the gastrointestinal (GI) tract, abnormalities in secretion, absorption, motility, and sensation have been implicated in functional gastrointestinal disorders (FGIDs). Ion channels play important roles in all these GI functions. Disruptions of ion channels' ability to conduct ions can lead to diseases called ion channelopathies. Channelopathies can result from changes in ion channel biophysical function or expression due to mutations, posttranslational modification, and accessory protein malfunction. Channelopathies are strongly established in the fields of cardiology and neurology, but ion channelopathies are only beginning to be recognized in gastroenterology. In this review, we describe the state of the emerging field of GI ion channelopathies. Several recent discoveries show that channelopathies result in alterations in GI motility, secretion, and sensation. In the epithelium, mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) or CFTR-associating proteins result in channelopathies with constipation or diarrhea as phenotypes. In the muscle, mutations in the SCN5A-encoded voltage-gated sodium channel NaV1.5 are associated with irritable bowel syndrome. In the sensory nerves, channelopathies of voltage-gated sodium channels NaV1.7 and NaV1.9 (encoded by SCN9A, SCN11A, respectively) manifest by either GI hyper- or hyposensation. Recent advances in structural biology and ion channel biophysics, coupled with personalized medicine, have fueled rapid discoveries of novel channelopathies and direct drug targeting of specific channelopathies. In summary, the emerging field of GI ion channelopathies has significant implications for functional GI disease stratification, diagnosis, and treatment.

Impact of Fluid–Structure Interaction on Direct Tumor-Targeting in a Representative Hepatic Artery System

Direct targeting of solid tumors with chemotherapeutic drugs and/or radioactive microspheres can be a treatment option which minimizes side-effects and reduces cost. Briefly, computational analysis generates particle release maps (PRMs) which visually link upstream particle injection regions in the main artery with associated exit branches, some connected to tumors. The overall goal is to compute patient-specific PRMs realistically, accurately, and cost-effectively, which determines the suitable radial placement of a micro-catheter for optimal particle injection. Focusing in this paper on new steps towards realism and accuracy, the impact of fluid-structure interaction on direct drug-targeting is evaluated, using a representative hepatic artery system with liver tumor as a test bed. Specifically, the effect of arterial wall motion was demonstrated by modeling a two-way fluid-structure interaction analysis with Lagrangian particle tracking in the bifurcating arterial system. Clearly, rapid computational evaluation of optimal catheter location for tumor-targeting in a clinical application is very important. Hence, rigid-wall cases were also compared to the flexible scenario to establish whether PRMs generated when based on simplifying assumptions could provide adequate guidance towards ideal catheter placement. It was found that the best rigid (i.e., time-averaged) geometry is the physiological one that occurs during the diastolic targeting interval.

MicroRNAs mark in the MLL-rearranged leukemia

MicroRNAs are short noncoding RNAs, known regulators of several signaling pathways cell differentiation and proliferation, development, and apoptosis, which are deregulated in acute leukemia. Mixed lineage leukemia (MLL) gene encodes a protein with histone methyltransferase activity, which is essential for the fine tuning of hematopoietic stem cell development and differentiation through the regulation of HOXA and MEIS1. MLL gene rearrangements characterize both acute myeloid and acute lymphoblastic leukemia associated with poor outcomes. MicroRNAs and MLL rearrangements are in tight association regulating each other expression, affecting cell cycle regulators, and composing complex networks with factors involved in leukemogenesis such as MYC and FLT3. MLL fusion genes are also capable of recruiting DNA methyltransferases at microRNAs promoters controlling their expression through epigenetic changes. Direct drug targeting of MLL has been difficult to achieve, and in this context, microRNA expression modulation represents an attractive approach.

Formulation of intranasal mucoadhesive temperature-mediated in situ gel containing ropinirole and evaluation of brain targeting efficiency in rats

Mucoadhesive temperature-mediated in situ gel formulations using chitosan and hydroxyl propyl methyl cellulose were used to enhance intranasal (i.n.) delivery of the dopamine D2 agonist ropinirole to the brain. Formulations were tested for gelation time, thermosensitivity, mucoadhesion, in vitro release and permeation, in vitro cytotoxicity, nasal clearance, in vivo bioavailability and brain uptake. In vivo bioavailability and brain uptake of ropinirole were assessed in albino rats following intranasal administration of 99mTc-ropinirole in situ gel, intranasal ropinirole solution and intravenous (i.v.) ropinirole solution. Radiolabeled ropinirole uptake was calculated as a fraction of administered dose. The absolute bioavailabilty of ropinirole from the temperature-mediated in situ gelling nasal formulation was 82%. The AUC 0–480 min in brain after nasal administration of ropinirole in situ gel was 8.5 times (869 ± 250% · min/g versus 102 ± 20% · min/g) that obtained following i.v. administration, this value was also considerably higher (869 ± 250% · min/g versus 281 ± 52% · min/g) than that achieved with intranasal ropinirole solution. High brain direct drug transport percentage (DTP; 90.36%) and drug targeting index (DTI) > 1 confirms direct nose to brain transport of the intranasal in situ gel formulation of ropinirole.

Intracellular immune dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome: state of the art and therapeutic implications

Background: Evidence in support of intracellular immune dysfunctions in people with myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) is accumulating, but few studies have addressed intracellular immunity as a potential therapeutic target. Objective: To provide an overview of our present understanding of intracellular immunity in ME/CFS, to relate the intracellular immune dysfunctions to other aspects of the illness like decreased natural killer cell function, the presence of infections and poor exercise performance, and to point to potential therapeutic targets. Methods: An in-depth review of the scientific literature of intracellular immunity in people with ME/CFS was performed. Results/conclusion: From the scientific literature it is concluded that proteolytic cleavage of the native RNase L enzyme is characteristic of the dysregulation of intracellular immunity in people with ME/CFS, but the origin of the dysregulation is speculative. There is increasing evidence for immune cell apoptosis and upregulation of various aspects of the 2′-5′ oligoadenylate (2-5A) synthetase/RNase L pathway in ME/CFS. This review provides the theoretical rationale for conducting studies examining the effectiveness of direct or indirect drug targeting of the 2-5A synthetase/RNase L pathway in ME/CFS patients.