Microneedle patch capable of dual drug release for drug delivery to brain tumors.

Primary brain tumors are mostly managed using surgical resection procedures. Nevertheless, in certain cases, a thin layer of tumors may remain outside of the resection process due to the possibility of permanent injury; these residual tumors expose patients to the risk of tumor recurrence. This study has introduced the use of microneedle patches implanted after surgery with a dual-release mechanism for the administration of doxorubicin. The proposed patches possess the capability to administer drugs directly to the residual tumors and initiate chemotherapy immediately following surgical procedures. Three-dimensional simulation of drug delivery to residual tumors in the brain has been performed based on a finite element method. The impact of four important parameters on drug delivery has been investigated, involving the fraction of drug released in the burst phase, the density of microneedles on the patch, the length of microneedles, and the microvascular density of the tumor. The simulation findings indicate that lowering the fraction of drug released in the initial burst phase reduces the maximum average concentration, but the sustained release that continues for a longer period, increasing the bioavailability of free drug. However, the area under curve (AUC) for different release rates remains unchanged due to the fact that an identical dose of drug is supplied in each instance. By increasing the density of microneedles on the patch, concentration accumulation is provided over an extensive region of tumor, which in turn induces more cancer cell death. A comparative analysis of various lengths reveals that longer microneedles facilitate profound penetration into the tumor layers and present better therapeutic response due to extensive area of the tumor which is exposure to chemotherapeutic drugs. Furthermore, high microvascular density, as a characteristic of the tumor microenvironment, is shown to have a significant impact on the blood microvessels drainage of drugs and consequently lower therapeutic response outcome. Our approach offers a computational framework for creating localized drug delivery systems and addressing the challenges related to residual brain tumors.

Charge-Switchable nanoparticles to enhance tumor penetration and accumulation.

Nanoparticle-based drug delivery systems hold potential in chemotherapy, but their limited accumulation in tumor tissues hinders effective drug concentration for combating tumor growth. Hence, altering the physicochemical properties of nanoparticles, particularly their surface charge, can enhance their performance. This study utilized a computational model to explore a nanoparticle drug delivery system capable of dynamically adjusting its surface charge. In the model, nanoparticles in the bloodstream were assigned a neutral or positive charge, which, upon reaching the tumor microenvironment, switched to a neutral or negative charge, and releasing chemotherapy drugs into the extracellular space. Results revealed that circulating nanoparticles with a positive surface charge, despite having a shorter circulation and high clearance rate compared to their neutral counterparts, could accumulate significantly in the tissue due to their high transvascular rate. After extravasation, neutralized surface-charged nanoparticles tended to accumulate only near blood microvessels due to their low diffusion rate, resulting in substantial released drug drainage back into the bloodstream. On the other hand, nanoparticles with a negative surface charge in the tumor's extracellular space, due to the reduction of nano-bio interactions, were able to penetrate deeper into the tumor, and increasing drug bioavailability by reducing the volume of drained drugs. Furthermore, the analysis suggested that burst drug release yields a higher drug concentration than sustained drug release, however their creation of bioavailability dependent on nanoparticle accumulation in the tissue. The study's findings demonstrate the potential of this delivery system and offer valuable insights for future research in this area.

Localized radiotherapy of solid tumors using radiopharmaceutical loaded implantable system: insights from a mathematical model.

Introduction: Computational models yield valuable insights into biological interactions not fully elucidated by experimental approaches. This study investigates an innovative spatiotemporal model for simulating the controlled release and dispersion of radiopharmaceutical therapy (RPT) using 177Lu-PSMA, a prostate-specific membrane antigen (PSMA) targeted radiopharmaceutical, within solid tumors via a dual-release implantable delivery system. Local delivery of anticancer agents presents a strategic approach to mitigate adverse effects while optimizing therapeutic outcomes. Methods: This study evaluates various factors impacting RPT efficacy, including hypoxia region extension, binding affinity, and initial drug dosage, employing a novel 3-dimensional computational model. Analysis gauges the influence of these factors on radiopharmaceutical agent concentration within the tumor microenvironment. Furthermore, spatial and temporal radiopharmaceutical distribution within both the tumor and surrounding tissue is explored. Results: Analysis indicates a significantly higher total concentration area under the curve within the tumor region compared to surrounding normal tissue. Moreover, drug distribution exhibits notably superior efficacy compared to the radiation source. Additionally, low microvascular density in extended hypoxia regions enhances drug availability, facilitating improved binding to PSMA receptors and enhancing therapeutic effectiveness. Reductions in the dissociation constant (KD) lead to heightened binding affinity and increased internalized drug concentration. Evaluation of initial radioactivities (7.1×107, 7.1×108, and 7.1×109 [Bq]) indicates that an activity of 7.1×108 [Bq] offers a favorable balance between tumor cell elimination and minimal impact on normal tissues. Discussion: These findings underscore the potential of localized radiopharmaceutical delivery strategies and emphasize the crucial role of released drugs relative to the radiation source (implant) in effective tumor treatment. Decreasing the proximity of the drug to the microvascular network and enhancing its distribution within the tumor promote a more effective therapeutic outcome. The study furnishes valuable insights for future experimental investigations and clinical trials, aiming to refine medication protocols and minimize reliance on in vivo testing.

Programmable intratumoral drug delivery to breast cancer using wireless bioelectronic device with electrochemical actuation.

OBJECTIVE: Breast cancer is a global health concern that demands attention. In our contribution to addressing this disease, our study focuses on investigating a wireless micro-device for intratumoral drug delivery, utilizing electrochemical actuation. Microdevices have emerged as a promising approach in this field due to their ability to enable controlled injections in various applications. METHODS: Our study is conducted within a computational framework, employing models that simulate the behavior of the microdevice and drug discharge based on the principles of the ideal gas law. Furthermore, the distribution of the drug within the tissue is simulated, considering both diffusion and convection mechanisms. To predict the therapeutic response, a pharmacodynamic model is utilized, considering the chemotherapeutic effects and cell proliferation. RESULTS: The findings demonstrate that an effective current of 3 mA, along with an initial gas volume equal to the drug volume in the microdevice, optimizes drug delivery. Microdevices with multiple injection capabilities exhibit enhanced therapeutic efficacy, effectively suppressing cell proliferation. Additionally, tumors with lower microvascular density experience higher drug concentrations in the extracellular space, resulting in significant cell death in hypoxic regions. CONCLUSIONS: Achieving an efficient therapeutic response involves considering both the characteristics of the tumor microenvironment and the frequency of injections within a specific time frame.

Improving tumor treatment through intratumoral injection of drug-loaded magnetic nanoparticles and low-intensity ultrasound.

The intratumoral injection of therapeutic agents responsive to external stimuli has gained considerable interest in treating accessible tumors due to its biocompatibility and capacity to reduce side effects. For the first time, a novel approach is explored to investigate the feasibility of utilizing low-intensity ultrasound in combination with intratumoral injection of drug-loaded magnetic nanoparticles (MNPs) to thermal necrosis and chemotherapy with the objective of maximizing tumor damage while avoiding harm to surrounding healthy tissue. In this study, a mathematical framework is proposed based on a multi-compartment model to evaluate the effects of ultrasound transducer's specifications, MNPs size and distribution, and drug release in response to the tumor microenvironment characteristics. The results indicate that while a higher injection rate may increase interstitial fluid pressure, it also simultaneously enhances the concentration of the therapeutic agent. Moreover, by increasing the power and frequency of the transducer, the acoustic pressure and intensity can be enhanced. This, in turn, increases the impact on accumulated MNPs, resulting in a rise in temperature and localized heat generation. Results have demonstrated that smaller MNPs have a lower capacity to generate heat compared to larger MNPs, primarily due to the impact of sound waves on them. It is worth noting that smaller MNPs have been observed to have enhanced diffusion, allowing them to effectively spread within the tumor. However, their smaller size also leads to rapid elimination from the extracellular space into the bloodstream. To summarize, this study demonstrated that the local injection of MNPs carrying drugs not only enables localized chemotherapy but also enhances the effectiveness of low-intensity ultrasound in inducing tissue thermal necrosis. The findings of this study can serve as a valuable and reliable resource for future research in this field and contribute to the development of personalized medicine.

A comparative study between conventional chemotherapy and photothermal activated nano-sized targeted drug delivery to solid tumor.

Delivery of chemotherapeutic medicines to solid tumors is critical for optimal therapeutic success and minimal adverse effects. We mathematically developed a delivery method using thermosensitive nanocarriers activated by light irradiation. To assess its efficacy and identify critical events and parameters affecting therapeutic response, we compared this method to bolus and continuous infusions of doxorubicin for both single and multiple administrations. A hybrid sprouting angiogenesis approach generates a semi-realistic microvascular network to evaluate therapeutic drug distribution and microvascular heterogeneity. A pharmacodynamics model evaluates treatment success based on tumor survival cell percentage. The study found that whereas bolus injection boosted extracellular drug concentration levels by 90%, continuous infusion improved therapeutic response due to improved bioavailability. Cancer cell death increases by 6% with several injections compared to single injections due to prolonged chemotherapeutic medication exposure. However, responsive nanocarriers supply more than 2.1 times more drug than traditional chemotherapy in extracellular space, suppressing tumor development longer. Also, controlled drug release decreases systemic side effects substantial through diminishing the concentration of free drug in the circulation. The primary finding of this work highlights the significance of high bioavailability in treatment response. The results indicate that responsive nanocarriers contribute to increased bioavailability, leading to improved therapeutic benefits. By including drug delivery features in a semi-realistic model, this numerical study sought to improve drug-bio interaction comprehension. The model provides a good framework for understanding preclinical and clinical targeted oncology study outcomes.

A spatiotemporal computational model of focused ultrasound heat-induced nano-sized drug delivery system in solid tumors.

Focused Ultrasound (FUS)-triggered nano-sized drug delivery, as a smart stimuli-responsive system for treating solid tumors, is computationally investigated to enhance localized delivery of drug and treatment efficacy. Integration of thermosensitive liposome (TSL), as a doxorubicin (DOX)-loaded nanocarrier, and FUS, provides a promising drug delivery system. A fully coupled partial differential system of equations, including the Helmholtz equation for FUS propagation, bio-heat transfer, interstitial fluid flow, drug transport in tissue and cellular spaces, and a pharmacodynamic model is first presented for this treatment approach. Equations are then solved by finite element methods to calculate intracellular drug concentration and treatment efficacy. The main objective of this study is to present a multi-physics and multi-scale model to simulate drug release, transport, and delivery to solid tumors, followed by an analysis of how FUS exposure time and drug release rate affect these processes. Our findings not only show the capability of model to replicate this therapeutic approach, but also confirm the benefits of this treatment with an improvement of drug aggregation in tumor and reduction of drug delivery in healthy tissue. For instance, the survival fraction of tumor cells after this treatment dropped to 62.4%, because of a large amount of delivered drugs to cancer cells. Next, a combination of three release rates (ultrafast, fast, and slow) and FUS exposure times (10, 30, and 60 min) was examined. Area under curve (AUC) results show that the combination of 30 min FUS exposure and rapid drug release leads to a practical and effective therapeutic response.

Stimuli-sensitive nano-drug delivery with programmable size changes to enhance accumulation of therapeutic agents in tumors.

Nano-based drug delivery systems hold significant promise for cancer therapies. Presently, the poor accumulation of drug-carrying nanoparticles in tumors has limited their success. In this study, based on a combination of the paradigms of intravascular and extravascular drug release, an efficient nanosized drug delivery system with programmable size changes is introduced. Drug-loaded smaller nanoparticles (secondary nanoparticles), which are loaded inside larger nanoparticles (primary nanoparticles), are released within the microvascular network due to temperature field resulting from focused ultrasound. This leads to the scale of the drug delivery system decreasing by 7.5 to 150 times. Subsequently, smaller nanoparticles enter the tissue at high transvascular rates and achieve higher accumulation, leading to higher penetration depths. In response to the acidic pH of tumor microenvironment (according to the distribution of oxygen), they begin to release the drug doxorubicin at very slow rates (i.e., sustained release). To predict the performance and distribution of therapeutic agents, a semi-realistic microvascular network is first generated based on a sprouting angiogenesis model and the transport of therapeutic agents is then investigated based on a developed multi-compartment model. The results show that reducing the size of the primary and secondary nanoparticles can lead to higher cell death rate. In addition, tumor growth can be inhibited for a longer time by enhancing the bioavailability of the drug in the extracellular space. The proposed drug delivery system can be very promising in clinical applications. Furthermore, the proposed mathematical model is applicable to broader applications to predict the performance of drug delivery systems.

Analysis of Magneto-Hyperthermia Duration in Nano-sized Drug Delivery System to Solid Tumors Using Intravascular-Triggered Thermosensitive-Liposome.

Computational models have been developed as a potential platform to identify bio-interactions that cannot be properly understood by experimental models. In the present study, a mathematical model has been employed to investigate the therapeutic response of drug-loaded thermosensitive liposome (TSL) following intravascular release paradigm. Thermal field created by an alternating magnetic field is utilized to release the drug within microvessels. Determining the time required for the application of magneto-hyperthermia is the main purpose of this study. Results show that applying a long-term continuous or pulsed hyperthermia can affect the concentration level of drugs in the extracellular space. The peak value of free and bound drug concentrations in the extracellular space is equal for all hyperthermia programs. Additionally, the concentrations of free and bound drugs are retained at a higher level in pulsed mode compared to the continuous mode (i.e., area under curve (AUC) of pulsed case is slightly higher than continuous case). However, there is no significant difference in bioavailability time. Hence, onset time of tumor growth is similar for different conditions. This study shows that the appropriate time to apply hyperthermia is post-bolus injection until reaching the peak concentration profile in extracellular space. Therefore, in clinical applications similar to the present study's circumstances, continuous hyperthermia for 30 min can be a better choice. This study can be a useful guideline for experimental studies to reduce the number of in vivo tests as well as for clinical trials to make the right decision to provide optimal medication programs.

Towards principled design of cancer nanomedicine to accelerate clinical translation.

Nanotechnology in medical applications, especially in oncology as drug delivery systems, has recently shown promising results. However, although these advances have been promising in the pre-clinical stages, the clinical translation of this technology is challenging. To create drug delivery systems with increased treatment efficacy for clinical translation, the physicochemical characteristics of nanoparticles such as size, shape, elasticity (flexibility/rigidity), surface chemistry, and surface charge can be specified to optimize efficiency for a given application. Consequently, interdisciplinary researchers have focused on producing biocompatible materials, production technologies, or new formulations for efficient loading, and high stability. The effects of design parameters can be studied in vitro, in vivo, or using computational models, with the goal of understanding how they affect nanoparticle biophysics and their interactions with cells. The present review summarizes the advances and technologies in the production and design of cancer nanomedicines to achieve clinical translation and commercialization. We also highlight existing challenges and opportunities in the field.

Engineered strategies to enhance tumor penetration of drug-loaded nanoparticles.

Nanocarriers have been widely employed in preclinical studies and clinical trials for the delivery of anticancer drugs. The most important causes of failure in clinical translation of nanocarriers is their inefficient accumulation and penetration which arises from special characteristics of tumor microenvironment such as insufficient blood supply, dense extracellular matrix, and elevated interstitial fluid pressure. Various strategies such as engineering extracellular matrix, optimizing the physicochemical properties of nanocarriers have been proposed to increase the depth of tumor penetration; however, these strategies have not been very successful so far. Novel strategies such as transformable nanocarriers, transcellular transport of peptide-modified nanocarriers, and bio-inspired carriers have recently been emerged as an advanced generation of drug carriers. In this study, the latest developments of nanocarrier-based drug delivery to solid tumor are presented with their possible limitations. Then, the prospects of advanced drug delivery systems are discussed in detail.

Computational modeling of thermal combination therapies by magneto-ultrasonic heating to enhance drug delivery to solid tumors.

For the first time, inspired by magnetic resonance imaging-guidance high intensity focused ultrasound (MR-HIFU) technology, i.e., medication therapy and thermal ablation in one session, in a preclinical setting based on a developed mathematical model, the performance of doxorubicin (Dox) and its encapsulation have been investigated in this study. Five different treatment methods, that combine medication therapy with mild hyperthermia by MRI contrast ([Formula: see text]) and thermal ablation via HIFU, are investigated in detail. A comparison between classical chemotherapy and thermochemistry shows that temperature can improve the therapeutic outcome by stimulating biological properties. On the other hand, the intravascular release of ThermoDox increases the concentration of free drug by 2.6 times compared to classical chemotherapy. The transport of drug in interstitium relies mainly on the diffusion mechanism to be able to penetrate deeper and reach the cancer cells in the inner regions of the tumor. Due to the low drug penetration into the tumor center, thermal ablation has been used for necrosis of the central areas before thermochemotherapy and ThermoDox therapy. Perfusion of the region around the necrotic zone is found to be damaged, while cells in the region are alive and not affected by medication therapy; so, there is a risk of tumor recurrence. Therefore, it is recommended that ablation be performed after the medication therapy. Our model describes a comprehensive assessment of MR-HIFU technology, taking into account many effective details, which can be a reliable guide towards the optimal use of drug delivery systems.

Effects of hypoxia and nanocarrier size on pH-responsive nano-delivery system to solid tumors.

One of the special features of solid tumors is the acidity of the tumor microenvironment, which is mainly due to the presence of hypoxic regions. Therefore, pH-responsive drug delivery systems have recently been highly welcomed. In the present study, a comprehensive mathematical model is presented based on extravascular drug release paradigm. Accordingly, drug delivery system using pH-responsive nanocarriers is taken into account to examine the impacts of hypoxic regions as well as the size of nanocarriers for cancerous cell-death. The extent of hypoxic regions is controlled by vascular density. This means that regions with very low vascular density represent regions of hypoxia. Using this mathematical model, it is possible to simulate the extracellular and intracellular concentrations of drug by considering the association/disassociation of the free drug to the cell-surface receptors and cellular uptake. Results show that nanocarriers with smaller sizes are more effective due to higher accumulation in the tumor tissue interstitium. The small size of the nanocarriers also allows them to penetrate deeper, so they can expose a larger portion of the tumor to the drug. Additionally, the presence of hypoxic regions in tumor reduces the fraction of killed cancer cells due to reduced penetration depth. The proposed model can be considered for optimizing and developing pH-sensitive delivery systems to reduce both cost and time of the process.

Enhancing Clinical Translation of Cancer Using Nanoinformatics.

Application of drugs in high doses has been required due to the limitations of no specificity, short circulation half-lives, as well as low bioavailability and solubility. Higher toxicity is the result of high dosage administration of drug molecules that increase the side effects of the drugs. Recently, nanomedicine, that is the utilization of nanotechnology in healthcare with clinical applications, has made many advancements in the areas of cancer diagnosis and therapy. To overcome the challenge of patient-specificity as well as time- and dose-dependency of drug administration, artificial intelligence (AI) can be significantly beneficial for optimization of nanomedicine and combinatorial nanotherapy. AI has become a tool for researchers to manage complicated and big data, ranging from achieving complementary results to routine statistical analyses. AI enhances the prediction precision of treatment impact in cancer patients and specify estimation outcomes. Application of AI in nanotechnology leads to a new field of study, i.e., nanoinformatics. Besides, AI can be coupled with nanorobots, as an emerging technology, to develop targeted drug delivery systems. Furthermore, by the advancements in the nanomedicine field, AI-based combination therapy can facilitate the understanding of diagnosis and therapy of the cancer patients. The main objectives of this review are to discuss the current developments, possibilities, and future visions in naoinformatics, for providing more effective treatment for cancer patients.

Controlled anti-cancer drug release through advanced nano-drug delivery systems: Static and dynamic targeting strategies.

Advances in nanomedicine, including early cancer detection, targeted drug delivery, and personalized approaches to cancer treatment are on the rise. For example, targeted drug delivery systems can improve intracellular delivery because of their multifunctionality. Novel endogenous-based and exogenous-based stimulus-responsive drug delivery systems have been proposed to prevent the cancer progression with proper drug delivery. To control effective dose loading and sustained release, targeted permeability and individual variability can now be described in more-complex ways, such as by combining internal and external stimuli. Despite these advances in release control, certain challenges remain and are identified in this research, which emphasizes the control of drug release and applications of nanoparticle-based drug delivery systems. Using a multiscale and multidisciplinary approach, this study investigates and analyzes drug delivery and release strategies in the nanoparticle-based treatment of cancer, both mathematically and clinically.

Nitrate improves hackberry seedling growth under cadmium application.

The environmental toxicity of heavy metals in particular cadmium is a public concern. Cadmium is toxic for all living organisms including plants; however, plant species may show different tolerance to the presence of cadmium in their root medium. Adopting practical strategies may reduce cadmium bioavailability or increase the plant tolerance. In the present study, interaction of nitrate was investigated on cadmium treatment in hackberry (Celtis australis L.) seedlings. Different levels of nitrate (0, 50 and 100 mg/L) and cadmium (0 and 5 mg/L) were applied to seedlings via irrigation water during two consequence years. The treatments were arranged in a factorial with completely randomized design in four replications. The results of ANOVA showed that the cadmium-nitrate interaction was significant on leaf Cd concentration and root dry weight at P = 0.01, and on carotenoids and leaf dry weight at P = 0.05, while it was not significant on the rest of traits. Application of cadmium had no significant effect on new shoot growth, leaf chlorophyll and leaf fresh weight; however, it significantly reduced stomatal water conductance and photosynthesis rate, while it increased leaf transpiration rate, root and stem fresh weights, leaf Cd and proline concentrations. Application of nitrate levels, on the other hand, constantly increased the leaf nitrate concentration, new shoot growth, leaf fresh and dry weights, root fresh weight, stomatal water conductance and photosynthesis rate, whereas it reduced the necrotic points of leaves. The results indicated that the growth characteristics of hackberry seedlings were mainly influenced by nitrate but not cadmium application, and this ornamental tree is a tolerant species to high soil Cd levels.