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.

Radiopharmaceutical transport in solid tumors via a 3-dimensional image-based spatiotemporal model.

Lutetium-177 prostate-specific membrane antigen (177Lu-PSMA)-targeted radiopharmaceutical therapy is a clinically approved treatment for patients with metastatic castration-resistant prostate cancer (mCRPC). Even though common practice reluctantly follows "one size fits all" approach, medical community believes there is significant room for deeper understanding and personalization of radiopharmaceutical therapies. To pursue this aim, we present a 3-dimensional spatiotemporal radiopharmaceutical delivery model based on clinical imaging data to simulate pharmacokinetic of 177Lu-PSMA within the prostate tumors. The model includes interstitial flow, radiopharmaceutical transport in tissues, receptor cycles, association/dissociation with ligands, synthesis of PSMA receptors, receptor recycling, internalization of radiopharmaceuticals, and degradation of receptors and drugs. The model was studied for a range of values for injection amount (100-1000 nmol), receptor density (10-500 nmol•l-1), and recycling rate of receptors (10-4 to 10-1 min-1). Furthermore, injection type, different convection-diffusion-reaction mechanisms, characteristic time scales, and length scales are discussed. The study found that increasing receptor density, ligand amount, and labeled ligands improved radiopharmaceutical uptake in the tumor. A high receptor recycling rate (0.1 min-1) increased radiopharmaceutical concentration by promoting repeated binding to tumor cell receptors. Continuous infusion results in higher radiopharmaceutical concentrations within tumors compared to bolus administration. These insights are crucial for advancing targeted therapy for prostate cancer by understanding the mechanism of radiopharmaceutical distribution in tumors. Furthermore, measures of characteristic length and advection time scale were computed. The presented spatiotemporal tumor transport model can analyze different physiological parameters affecting 177Lu-PSMA delivery.

Spatiotemporal modeling of radiopharmaceutical transport in solid tumors: Application to 177Lu-PSMA therapy of prostate cancer.

BACKGROUND AND OBJECTIVE: 177Lu-labeled prostate-specific membrane antigen (PSMA) radiopharmaceutical therapy (RPT) represents a pivotal advancement in addressing prostate cancer. However, existing therapies, while promising, remain incompletely understood and optimized. Computational models offer potential insights into RPTs, aiding in clinical drug delivery enhancement. In this study, we investigate the impact of various physiological parameters on the delivery of 177Lu-PSMA-617 RPT using the convection-diffusion-reaction (CDR) model. METHODS: Our investigation encompasses tumor geometry and surrounding tissue, characterized by well-defined boundaries and initial conditions. Utilizing the finite element method, we solve governing equations across a range of parameters: dissociation constant KD (1, 0.1, 0.01 [nM]), internalization rate (0.01-0.0001 [min-1]), diverse tumor shapes, and variable necrotic zone sizes. This model can provide an accurate analysis of radiopharmaceutical delivery from the injection site to the tumor cell, including drug transport in the vascular, interstitial, and intracellular spaces, and considering important parameters (e.g., drug extravasation from microvessels or to lymphatic vessels, the extracellular matrix, receptors, and intracellular space). RESULTS: Our findings reveal significant enhancements in tumor-absorbed doses as KD decreases. This outcome can be attributed to the higher affinity of radiopharmaceuticals for PSMA receptors as KD diminishes, facilitating a more efficient binding and retention of the therapeutic agent within the tumor microenvironment. Additionally, tumor-absorbed doses for KD ∼ 1 [nM] show an upward trend with higher internalization rates. This observation can be rationalized by considering that a greater internalization rate would result in a higher proportion of radiopharmaceuticals being taken up by tumor cells after binding to receptors on the cell surface. Notably, tumor shape and necrotic zone size exhibit limited influence on tumor absorbed dose. CONCLUSIONS: The present study employs the CDR model to explore the role of physiological parameters in shaping 177Lu-PSMA-617 RPT delivery. These findings provide insights for improving prostate cancer therapy by understanding radiopharmaceutical transport dynamics. This computational approach contributes to advancing our understanding of radiopharmaceutical delivery mechanisms and has implications for enhancing treatment efficacy.

Investigation of the effects of porosity and volume fraction on the atomic behavior of cancer cells and microvascular cells of 3DN5 and 5OTF macromolecular structures during hematogenous metastasis using the molecular dynamics method.

BACKGROUND AND OBJECTIVE: The molecular dynamics (MD) simulation is a powerful tool for researching how cancer patients are treated. The efficiency of many factors may be predicted using this approach in great detail and with atomic accuracy. METHODS: The MD simulation method was used to investigate the impact of porosity and the number of cancer cells on the atomic behavior of cancer cells during the hematogenous spread. In order to examine the stability of simulated structures, temperature and potential energy (PE) values are used. To evaluate how cell structure has changed, physical parameters such as gyration radius, interaction force, and interaction energy are also used. RESULTS: The findings demonstrate that the samples' gyration radius, interaction energy, and interaction force rose from 41.33 Å, -551.38 kcal/mol, and -207.10 kcal/mol Å to 49.49, -535.94 kcal/mol, and -190.05 kcal/mol Å, respectively, when the porosity grew from 0% to 5%. Also, the interaction energy and force in the samples fell from -551.38 kcal/mol and -207.10 kcal/mol to -588.03 kcal/mol and -237.81 kcal/mol Å, and the amount of gyration radius reduced from 41.33 to 37.14 Å as the number of cancer cells rose from 1 to 5 molecules. The strength and stability of the simulated samples will improve when the radius of gyration is decreased. CONCLUSIONS: Therefore, high accumulation of cancer cells will make them resistant to atomic collapse. It is expected that the results of this simulation should be used to optimize cancer treatment processes further.

pH-sensitive loading/releasing of doxorubicin using single-walled carbon nanotube and multi-walled carbon nanotube: A molecular dynamics study.

BACKGROUND AND OBJECTIVE: Doxorubicin is one of the drugs used to treat cancer, and many studies have been conducted to control its release. In this study, carbon nanotubes have been proposed as a doxorubicin carrier, and the effect of carboxyl functional group on the controlled release of doxorubicin has been studied. METHODS: This study has been done by molecular dynamics simulation and was based on changing the pH as a mechanism controller. RESULTS: This work is intended to test the efficacy of this drug carrier for the release of doxorubicin. A comparison was also made between single-walled and double-walled carbon nanotubes to answer the question of which one can be a better carrier for doxorubicin. The study of DOXORUBICIN adsorption and release showed that the DOXORUBICIN adsorption on single-walled carbon nanotube and multi-walled carbon nanotube in neutral pH was stronger than it was in acidic pH, which could be due to the electrostatic interactions between the carboxyl group of nanotubes and DOXORUBICIN. Based on this and according to the investigation of hydrogen bonds, diffusion coefficients, and other results it was clear that the drug release in acidic pH was appropriate for body conditions. Since cancer tissues pH is acidic, this shows the suitability of carbon nanotube in drug delivery and DOXORUBICIN release in cancer tissues. In addition, it was shown that the blood pH (pH = 7) is suitable for DOXORUBICIN loading on the carbon nanotube and carbon nanotube-DOXORUBICIN linkage remained stable at this pH; accordingly, the carbon nanotube could deliver DOXORUBICIN in blood quite well and release it in cancerous tissues. This suggests the carbon nanotubes as a promising drug carrier in the cancer therapy which can be also investigated in experiments. CONCLUSION: It was revealed that the bonds between multi-walled carbon nanotube and DOXORUBICIN was stronger and this complex had a slower release in the cancer tissues compared to the single-walled carbon nanotube; this can be regarded as an advantage over the single-walled carbon nanotube in the DOXORUBICIN delivery and release.

Investigation of thermal properties of DNA structure with precise atomic arrangement via equilibrium and non-equilibrium molecular dynamics approaches.

BACKGROUND AND OBJECTIVE: Thermal conductivity of Deoxyribonucleic acid molecules is important for nanotechnology applications. Theoretical simulations based on simple models predict thermal conductivity for these molecular structures. METHODS: In this work, we calculate the thermal properties of Deoxyribonucleic acid with precise atomic arrangement via equilibrium and non-equilibrium molecular dynamics approaches. In these methods, each Deoxyribonucleic acid molecule is represented by C, N, O, and P atoms and implemented dreidng potential to describe their atomic interactions. RESULTS: Our calculated rate for thermal conductivity via equilibrium and non-equilibrium molecular dynamics methods is 0.381 W/m K and 0.373 W/m K, respectively. By comparing results from these two methods, it was found that the results from equilibrium and non-equilibrium molecular dynamics methods are identical, approximately. On the other hand, the number of DNA molecules and the equilibrium temperature of the simulated structures were important factors in their thermal conductivity rates, and their thermal conductivity was calculated at 0.323 W/m K-0.381 W/m K intervals for equilibrium and 0.303 W/m K-0.373 W/m K interval for non-equilibrium calculations. CONCLUSIONS: These results are in good agreement with thermal conductivity calculation with other research groups.