Remote Drug Delivery Research Articles

Modifying a mini drone for remote drug delivery for wildlife medicine

Remote drug delivery is an essential tool for administering medication to wildlife. However, the conventional method, the dart gun, has limitations in terms of injection distance, posing risks for operators. This study aimed to modify a mini drone equipped with a dart syringe and delivery system for use with large wildlife. A commercial mini drone was modified to release a syringe dart using a vertical gravity-based delivery system. The performance of the drone and delivery system was evaluated based on accuracy to the target and penetration ability through pig skin. The evaluation compared a dart with or without a plastic shell, with tests conducted both indoors and outdoors. The results indicated that the higher the drone's flight, the more the dart tended to deviate from the target. In outdoor tests, a syringe dart without a shell showed greater accuracy than a dart with a shell. Regarding penetration ability, only a dart without a shell had a 100% success rate at a maximum height of 5 metres, with an overall statistical difference (P = 0.01). In conclusion, this study represents the first scientific validation of using mini drones for remote drug injections that could be used in large wildlife medicine.

Evaluating a Controlled Electromagnetic Launcher for Safe Remote Drug Delivery

Biologists and veterinarians rely on dart projectors to inject animals with drugs, take biopsies from specimens, or inject tracking chips. Firearms, air guns, and other launchers are limited in their ability to precisely control the kinetic energy of a projectile, which can injure the animal if too high. In order to improve the safety of remote drug delivery, a lidar-modulated electromagnetic launcher and a soft drug delivery dart were prototyped. A single-stage revolver coilgun and soft dart were designed and tested at distances up to 8 m. With a coil efficiency of 2.25%, the launcher could consistently deliver a projectile at a controlled kinetic energy of 1.00 ± 0.006 J and an uncontrolled kinetic energy of 2.66 ± 0.076 J. Although modifications to charging time, sensors, and electronics could improve performance, our launcher performed at the required level at the necessary distances. The precision achieved with commercial components enables many other applications, from law enforcement to manufacturing.

A mesoporous magnetothermal nanopomegranate with acid-tolerant hierarchical structure for remote controlled drug delivery

Developing acid-tolerant magnetothermal nanoplatform with robust drug loading capacity for remote controlled drug release is challenging in the harsh acid environment of stomach. Herein, a nanopomegranate-type magnetothermal controllable drug release platform (FeCo@G@MSN), consisted of magnetothermal convertor (graphene-isolated FeCo nanocrystal core, FeCo@G) and drug reservoir (mesoporous silica, MSN), with acid-tolerant hierarchical structure was developed. Benefiting from the acid tolerance of graphene and MSN, FeCo@G@MSN was stable in 1 M hydrochloric acid for more than 12 h. The nanopomegranate-type hierarchical structure endowed FeCo@G@MSN with high saturation magnetization (114.9 emu/g) to generate a magnetothermal effect and large specific surface area (293.7 m2/g) to provide ample space for drug loading. As a proof of concept, a heat-triggered nitric oxide (NO) precursor was loaded, and NO were controlled released by breaking of S-NO bonds through localized heat derived from magnetothermal effect of FeCo@G, resulting in an inhibition effect towards Helicobacter pylori. A chemotherapeutic drug (doxorubicin, DOX) was also loaded and controlled released by breaking of hydrogen bonds between silica and DOX under remote an alternating magnetic field, thus exhibiting an inhibition effect towards gastric cancer cells. This work provides an efficient strategy to exploit magnetothermal controlled drug release platform and offers inspiration for the treatment of gastric diseases.

Characterization and antitumor effect of doxorubicin-loaded Fe3O4-Au nanocomposite synthesized by electron beam evaporation for magnetic nanotheranostics.

Magnetic nanocomposites (MNC) are promising theranostic platforms with tunable physicochemical properties allowing for remote drug delivery and multimodal imaging. Here, we developed doxorubicin-loaded Fe3O4-Au MNC (DOX-MNC) using electron beam physical vapor deposition (EB-PVD) in combination with magneto-mechanochemical synthesis to assess their antitumor effect on Walker-256 carcinosarcoma under the influence of a constant magnetic (CMF) and electromagnetic field (EMF) by comparing tumor growth kinetics, magnetic resonance imaging (MRI) scans and electron spin resonance (ESR) spectra. Transmission (TEM) and scanning electron microscopy (SEM) confirmed the formation of spherical magnetite nanoparticles with a discontinuous gold coating that did not significantly affect the ferromagnetic properties of MNC, as measured by vibrating-sample magnetometry (VSM). Tumor-bearing animals were divided into the control (no treatment), conventional doxorubicin (DOX), DOX-MNC and DOX-MNC + CMF + EMF groups. DOX-MNC + CMF + EMF resulted in 14% and 16% inhibition of tumor growth kinetics as compared with DOX and DOX-MNC, respectively. MRI visualization showed more substantial tumor necrotic changes after the combined treatment. Quantitative analysis of T2-weighted (T2W) images revealed the lowest value of skewness and a significant increase in tumor intensity in response to DOX-MNC + CMF + EMF as compared with the control (1.4 times), DOX (1.6 times) and DOX-MNC (1.8 times) groups. In addition, the lowest level of nitric oxide determined by ESR was found in DOX-MNC + CMF + EMF tumors, which was close to that of the muscle tissue in the contralateral limb. We propose that the reason for the relationship between the observed changes in MRI and ESR is the hyperfine interaction of nuclear and electron spins in mitochondria, as a source of free radical production. Therefore, these results point to the use of EB-PVD and magneto-mechanochemically synthesized Fe3O4-Au MNC loaded with DOX as a potential candidate for cancer magnetic nanotheranostic applications.

Electrospun PCL/PVA Coaxial Nanofibers with Embedded Titanium Dioxide and Magnetic Nanoparticles for Stabilization and Controlled Release of Dithranol for Therapy of Psoriasis

Dithranol is one of the oldest and most efficient drugs used in the treatment of psoriasis. One of the challenges with using dithranol is its photostability, because it easily degrades when exposed to light. This study investigated the potential of coaxial core-sheath PCL/PVA nanofibers as a dual-functional system for enhancing dithranol photostability and remote-controlled drug delivery for psoriasis therapy. We have shown that coaxial nanofibers with titanium oxide nanoparticles (reflecting and absorbing ultra-violet light) in the PVA-based sheath part of the nanofibers can increase dithranol photostability. Incorporation of dithranol and magnetic nanoparticles into a PCL-based core of the nanofibers enables dithranol release control via an external radio-frequency field. The application of a radio-frequency field generates heat that can be used to control the release rate of drugs. Our approach therefore offers a non-invasive and remotely controlled drug release system that hold promise for the development of new topical formulations for psoriasis treatment using dithranol.

Giant magnetoelectricity in soft materials using hard magnetic soft materials

Imagine a material that will produce electricity via a contactless, wireless signal. Further, we hope that this material is capable of large deformation reminiscent of soft robots and is soft enough to conform to irregular or curved geometries. This would all be possible if soft magnetoelectric materials were available; paving the way for applications such as remote drug delivery, energy harvesting, soft robots, multiple state memories among others. Here, for the first time, using the concept of hard magnetic soft matter in combination with electrets, we design and create a soft magnetoelectric material that exhibits an extremely strong, self-biased magnetoelectric effect. Further, using programmable pattern of deposition of magnetic dipoles and charges, we report a giant magnetoelectric coefficient in an ultra-soft deformable material that retains its strength even under infinitesimal external fields and at low frequencies.

Application of fuzzy learning in IoT-enabled remote healthcare monitoring and control of anesthetic depth during surgery

Smart remote patient monitoring and early disease diagnosis systems have made huge progresses after the introduction of Internet of Things (IoT) and Artificial Intelligence (AI) concepts. This paper proposes an AI-enabled IoT system to monitor and adjust the depth of anesthesia via network channels. More precisely, fuzzy learning systems are employed to develop a control system for the depth of anesthesia in surgeries. This scheme is composed of variable structure control and adaptive type-II fuzzy systems. Therefore, the controller is adaptive and robust to any perturbations and disturbances that may happen during a patient’s surgery. The adaptive type-II fuzzy system is designed as an intelligent online estimator to approximate patient model uncertainties. This estimation helps in boosting the performance of the variable structure control system. An artificial neuron is also designed to reduce chattering for the proposed control system. The designed control system can efficiently adjust the anesthesia drug infusion rate and regulate the Bispectral index. The networked structure of the proposed system makes remote tuning of drug infusion possible. Performance of the designed controller is evaluated on several patient models. Simulation results confirm the validity and effectiveness of the proposed remote drug delivery system.

Self-assembly of hydroxyapatite around Ti3C2 MXene/gold nanorods for efficient remotely triggered drug delivery

Ti3C2 MXene/gold nanorods (Ti3C2@AuNRs) nanosheets, a novel sandwich-like nanohybrids, have attracted extensive attention in the biomedical field due to its synergistically enhanced near-infrared (NIR) responsiveness and strong absorption in NIR region. In this study, hydroxyapatite (HAP) was self-assembled in situ around Ti3C2@AuNRs core and then combined with polydopamine (PDA) to prepare NIR-/pH- dual responsive Ti3C2@AuNRs/HAP/PDA nanocomposites. The obtained Ti3C2@AuNRs/HAP/PDA nanocomposites exhibited prominent photothermal conversion efficiency (38.6%) due to the synergistically enhanced NIR-responsive of Ti3C2@AuNRs. Ti3C2@AuNRs/HAP/PDA nanocomposites displayed excellent drug loading capacity (88.3%) for antitumor drug doxorubicin hydrochloride (DOX) because of the electrostatic interaction of negatively charged HAP nanorods and positively charged DOX, along with the distinct adhesiveness of PDA. In addition, the disintegration of HAP under acid medium and the strong NIR absorption of Ti3C2@AuNRs endowed the Ti3C2@AuNRs/HAP/PDA nanocomposites with pH-/NIR-dual responsive drug release behavior. In this paper, a feasible method is presented to prepare Ti3C2-based drug carriers with high drug loading capacity and remarkable multi-responsive drug release properties, which holds great promise in the field of remote controlled drug delivery and photothermal therapy.

Exploration of double-dart injection technique as a supplemental application for remote drug delivery system for zoo and wild animals.

Background and Aim:Remote drug delivery has become an essential tool for safely delivering medication and vaccines to free-ranging, non-domestic, or dangerous animals. All dart guns currently use a single dart per injection, and it might occasionally be not practical with large animals. Shooting the dart more than once on an animal may cause flight, injury, stress, and ultimately unsuccessful delivery. Furthermore, purchasing many dart guns and hiring and training more staff may be unfeasible in developing countries. Therefore, employing the double-dart injection technique may help reduce the cost of operation, save time for capturing animals, minimize stress and injury, and improve animal welfare. The objectives of this study were to test the possibility of using the double-dart injection technique and optimizing the guidelines for this procedure.Materials and Methods:A standard brand-calibrated darting rifle was used to deliver the darts to the target board constructed from paper, polypropylene, and ethylene-vinyl acetate foam. The shot stage and shooter were fixed, and the shooting range was 5-20 m. The pressure of the gun was varied according to a company’s recommendation. The single dart (control dart) was first shot to the target point, and then the double darts were shot 3 times for each condition. The experiment was done in the field with no wind. The inclusion criteria were that two darts must hit the target and not penetrate the target board deeply. The distances between the control dart and double darts (first and second darts) and between each dart of the double darts were measured, and the standard curve graphs and formulas were created.Results:The results showed that the distance between the control dart and the double darts was shortened as the pressure was increased. All double-dart injections hit the target below the control dart. We were able to create many formulas to predict the optimal gun pressure and aim point for double-dart injection in each shot range. It usually requires more pressure settings than a single-dart injection, particularly the long shot range. It also needs to aim the target point above the original point.Conclusion:Double-dart injection technique can be used efficiently in 5-20 m distance, and it usually requires increasing the pressure from the company’s recommendation and adjusting the injecting point.

Chitosan derivatives functionalized dual ROS-responsive nanocarriers to enhance synergistic oxidation-chemotherapy

The efficient triggering of prodrug release has become a challengeable task for stimuli-responsive nanomedicine utilized in cancer therapy due to the subtle differences between normal and tumor tissues and heterogeneity. In this work, a dual ROS-responsive nanocarriers with the ability to self-regulate the ROS level was constructed, which could gradually respond to the endogenous ROS to achieve effective, hierarchical and specific drug release in cancer cells. In brief, DOX was conjugated with MSNs via thioketal bonds and loaded with β-Lapachone. TPP modified chitosan was then coated to fabricate nanocarriers for mitochondria-specific delivery. The resultant nanocarriers respond to the endogenous ROS and release Lap specifically in cancer cells. Subsequently, the released Lap self-regulated the ROS level, resulting in the specific DOX release and mitochondrial damage in situ, enhancing synergistic oxidation-chemotherapy. The tumor inhibition Ratio was achieved to 78.49%. The multi-functional platform provides a novel remote drug delivery system in vivo.

Partially Reversible Immobilization of Free-Ranging Huemul Deer (Hippocamelus bisulcus) with Medetomidine-Ketamine and Atipamezole.

A combination of intramuscular medetomidine and ketamine was used to immobilize 46 free-ranging huemul deer (Hippocamelus bisulcus) with a remote drug delivery system in Chilean Patagonia for tagging and biological sampling. Captures occurred in May-October of 2005-09 between fall and early spring in the southern hemisphere. An initial dose of 6.6 mg medetomidine and 185 mg ketamine was adjusted after 17 captures to 3 mg and 200 mg, respectively, in the 29 remaining deer. Mean±SD adjusted dose was 0.042±0.012 mg/kg of medetomidine and 2.929±0.427 mg/kg of ketamine. Inductions were calm and the mean±SD time to sternal recumbency was 10.3±10.1 min. Palpebral reflex and jaw tone were present during immobilization. Atipamezole at 5 mg/mg of medetomidine was administered intramuscularly for reversal after 55.3±18.8 min procedure time. Recoveries were smooth and mean±SD time to standing was 10.2±3.3. All immobilized animals were hypoxemic by pulse oximetry (blood oxygen saturation approximately 81%). Three animals that developed apnea were resuscitated through chest compression and atipamezole administration, another regurgitated during capture, and all developed tachypnea. The combination of medetomidine-ketamine and atipamezole can be used for partially reversible immobilization of huemul, but supplemental oxygen should be administered, blood oxygenation should be monitored, and equipment for intubation and manual ventilation should be available.

Key Points in Remote-Controlled Drug Delivery: From the Carrier Design to Clinical Trials.

The increased research activity aiming at improved delivery of pharmaceutical molecules indicates the expansion of the field. An efficient therapeutic delivery approach is based on the optimal choice of drug-carrying vehicle, successful targeting, and payload release enabling the site-specific accumulation of the therapeutic molecules. However, designing the formulation endowed with the targeting properties in vitro does not guarantee its selective delivery in vivo. The various biological barriers that the carrier encounters upon intravascular administration should be adequately addressed in its overall design to reduce the off-target effects and unwanted toxicity in vivo and thereby enhance the therapeutic efficacy of the payload. Here, we discuss the main parameters of remote-controlled drug delivery systems: (i) key principles of the carrier selection; (ii) the most significant physiological barriers and limitations associated with the drug delivery; (iii) major concepts for its targeting and cargo release stimulation by external stimuli in vivo. The clinical translation for drug delivery systems is also described along with the main challenges, key parameters, and examples of successfully translated drug delivery platforms. The essential steps on the way from drug delivery system design to clinical trials are summarized, arranged, and discussed.

In situ self-assembly of gold nanorods with thermal-responsive microgel for multi-synergistic remote drug delivery

In situ self-assembly of gold nanorods with thermal-responsive microgel for multi-synergistic remote drug delivery

Real-Time Teleoperation of Magnetic Force-Driven Microrobots With 3D Haptic Force Feedback for Micro-Navigation and Micro-Transportation

Untethered mobile microrobots controlled by an external magnetic gradient field can be employed as advanced biomedical applications inside the human body such as cell therapy, micromanipulation, and noninvasive surgery. Haptic technology and telecommunication, on the other hand, can extend the potentials of untethered microrobot applications. In those applications, users can communicate with the robot operating system remotely to manipulate microrobots with haptic feedback. Haptic sensations artificially constructed by the wirelessly communicated information can assist human operators to experience forces while controlling the microrobots. The proposed system is composed of a haptic device and a magnetic tweezer system, both of which are integrated through a teleoperation technique based on network communication. Users can control the microrobots remotely and feel the haptic interactions with the remote environment in real-time. The 3D haptic environment is reconstructed dynamically by a model-free haptic rendering algorithm using a 2D planar image input of the microscope. The interaction between microrobots and environmental objects is haptically rendered as 3D objects to achieve spatial haptic operation with obstacle avoidance. Moreover, path generation and path guidance forces provide virtual interaction for human users to manipulate the microrobot by following the near-optimal path in path-following tasks. The potential applications of the presented system are medical remote treatment in different sites, remote drug delivery by avoiding physically penetrating through the skin, remotely-controlled cell manipulations, and biopsy without a biopsy needle.

Potential remote drug delivery failures due to temperature-dependent viscosity and drug-loss of aqueous and emulsion-based fluids

The ability to inject wild animals from a distance using remote drug delivery systems (RDDS) is one of the most effective and humane practices in wildlife management. Several factors affect the successful administration of drugs using RDDS. For example, temperature-dependent viscosity change in aqueous (Newtonian) or water-in-oil emulsion (non-Newtonian) fluids, commonly used in tranquilizer and adjuvant-based vaccines, respectively, can potentially result in drug delivery failure. To better understand impacts due to viscosity changes, we investigated the fluid dynamics and ballistics involved in remote drug delivery. Our research was divided into two phases: we investigated the viscosimetric physics in the first phase to determine the fluid behavior under different temperature settings, simulating recommended storage temperature (7ºC), plus an ambient temperature (20ºC). In the second phase of our study, we assessed the drug delivery efficiency by specialized darts, using a precision CO2 projector and a blowgun. Efficiency assessment was done by comparing the original drug volume with the actual volume injected after firing the dart into a fresh pork hide mounted on a ballistic gel. Before testing, we configured the required minimum impact velocity for our parameters and intramuscular injection (determined as ˃ 40 m/sec). All executed dart-deployments performed satisfactorily, despite initial concerns of potential incomplete drug delivery, however, noteworthy drug loss was observed (˃10%) associated with drug residues in syringe/dart dead space and within the transfer needle. This could potentially result in inaccurate dosing depending on the drug used. Furthermore, the use of a blowgun for remote drug delivery (>3m) is discouraged, especially when using specialized darts, as the required minimum dart velocity for adequate penetration is difficult to reach, in addition to a loss of precision during targeting.

Cellular Uptake Study of Antimycotic-Loaded Carriers Using Imaging Flow Cytometry and Confocal Laser Scanning Microscopy

The development and optimization of remote drug delivery systems is a flourishing branch of pharmacy. There is a number of requirements for such systems, among which are biocompatibility and, in some cases, the efficiency of intracellular delivery. The cellular survival after the carrier entrapment is an indirect evidence of biocompatibility of the applied system. The internalization process, as well as main characteristics of carriers themselves can be investigated by imaging flow cytometry and confocal laser scanning microscopy. However, the protocols of carriers’ characterization and the assessment of their uptake efficiency are needed to be improved. In this work, we optimized the evaluation technic for particles’ internalization process by imaging flow cytometry. The confocal laser scanning microscopy was applied as a control method of the particle uptake investigation. The comparative research showed a good correlation between the obtained data. Thus, the high throughput capability of imaging flow cytometry together with the optimized technic of the determination of particle localization inside the cell will further allow us to estimate faster the internalization efficiency of the object under investigation.

Chemical immobilization of free-living capybaras (Hydrochoerus hydrochaeris) using ketamine-dexmedetomidine combination and a remote drug delivery system

Capturing wild capybaras for scientific projects, population control or medical interventions is a growing necessity. With this study, we intended to evaluate a Ketamine/Dexmedetomidine as a reversible chemical restraint in free-ranging synanthropic capybaras, seeking enhanced anesthetic and recovery characteristics while testing a specialized remote drug delivery system (RDDS). For this purpose, 18 adult capybaras (male n = 8; females n = 10) (67.3 ± 9.45 kg), prior to chemical restraint, were physically confined, subsequently darted intramuscularly with 9 mg kg-1 ketamine and 0,005 mg kg-1 dexmedetomidine. Post-intervention, 0,005 mg kg-1 atipamezole, administered IM, was used as a reversal agent (RA), (n = 5). Anesthetic effects were recorded as latency period (LP I/first observed effects) (LP II /lateral recumbency plus time to handle the animal). Recovery time was divided into (R1/no RA, fully recovered/ready for release), (R2a/R2b, with RA, time to ambulant position plus time to full recovery/release, respectively). Vital signs were recorded at a 15-minute interval. GraphPad Prism 8.1.1 was used to perform unpaired t-test, with a p-value ˂ 0,05 considered significant. Results: Mean LP I: 3 ± 1 min.; LP II: 10 ± 2 min. Procedure duration: 49 ± 5 min. Recovery time without RA, (R1): 55 ± 15 min., compared to 18 min., with RA (R2a) to ambulant position (with severe discoordination), requiring additional time until full recovery (ready for release): ± 45 min (R2b). Total time, to release (R2a/b): mean ± SD = 67 ± 13.85 min. Concluding for clinical relevance that the association of Ketamine and Dexmedetomidine performed satisfactorily, providing effective sedation and analgesia, and relative short latency periods. Used RA did not shorten total recovery time significantly (P-value = 0,7328). Adverse effects such as the risk of acute cecal tympany, due to the lack of pre-anesthetic fasting, concurrent to collateral effects of injectable and volatile anesthetics on the motility of the digestive tract, and induced bradycardia/hyperthermia warrant extra caution. The employed RDDS provided reliable drug delivery under field conditions.

Spatiotemporal Control Release of pH-Responsive Polymeric Micelles via Photochemically Induced Proton Generation.

Spatiotemporal control is important in biomedical applications for guided drug delivery and release at desired location. Herein, we provide a new remote-controlled drug delivery system by simply combining pH-responsive polymeric micelles [poly(ethylene glycol)-block-poly(2-(diisopropylamino) ethyl methacrylate), mPEG-b-PDPA] with photoacid generators (PAGs) to actively control the local pH variation via photochemical induced proton generation. The dual chemotherapy drug doxorubicin- (DOX) and PAG-loaded micelles (P-PD) possess good storage stability, high drug loading content, and excellent light remote-controlled drug release behavior. An in vitro cytotoxicity study shows P-PD micelles have better cell growth inhibition efficiency under light irradiation as compared to free DOX, individual DOX, or PAG-loaded micelles. Intracellular DOX distribution confirms the more drugs release upon light irradiation. These results indicate remote-controlled drug release renders the drugs more efficiently to serve their function and reduce the need for high dosage. We believe this P-PD micelle is a promising spatiotemporally controlled drug delivery system for cancer therapy.

Remotely controlled nanofluidic implantable platform for tunable drug delivery

Chronic diseases such as hypertension and rheumatoid arthritis are persistent ailments that require personalized lifelong therapeutic management. However, the difficulty of adherence to strict dosing schedule compromises therapeutic efficacy and safety. Moreover, the conventional one-size-fits-all treatment approach is increasingly challenged due to the intricacies of inter- and intra-individual variabilities. While accelerated technological advances have led to sophisticated implantable drug delivery devices, flexibility in dosage and timing modulation to tailor precise treatment to individual needs remains an elusive goal. Here we describe the development of a subcutaneously implantable remote-controlled nanofluidic device capable of sustained drug release with adjustable dosing and timing. By leveraging a low intensity electric field to modify the concentration driven diffusion across a nanofluidic membrane, the rate of drug administration can be increased, decreased or stopped via Bluetooth remote command. We demonstrate in vitro the release modulation of enalapril and methotrexate, first-line therapeutics for treatment of hypertension and rheumatoid arthritis, respectively. Further, we show reliable remote communication and device biocompatibility via in vivo studies. Unlike a pulsatile release regimen typical of some conventional controlled delivery systems, our implant offers a continuous drug administration that avoids abrupt fluctuations, which could affect response and tolerability. Our system could set the foundation for an on-demand delivery platform technology for long term management of chronic diseases.

The remote controlled drug delivery system combing photothermal therapy with chemotherapy

The remote controlled drug delivery system combing photothermal therapy with chemotherapy