(470c) A New Patient-Specific Targeted Pulmonary Drug Delivery Method to Treat Lung Cancer Using E-Cigarette Technology

Keywords: Targeted Pulmonary Drug Delivery; Computational Fluid-Particle Dynamics (CFPD); Precise Treatment Plan

1. Background

Lung cancer strikes 225,000 people every year and accounts for $12 billion in health care costs in the United States. Inhalation of therapeutic drug aerosols is now becoming a novel way to administer micro/nano- particles or vapors with anti-cancer agents to treat lung cancer as well as other lung and systemic diseases. However, due to certain design deficiencies, existing pulmonary drug delivery devices still have poor efficiencies for delivering drugs to the lung tumor sites. Major portions of the aggressive medicine deposit on healthy tissues, which causes severe side effects and induces extra health care expenses. Therefore, it is an urgent need to understand the drug particle dynamics better and develop a revolutionary patient-specific pulmonary drug delivery method and device to significantly improve therapeutic outcomes by improving drug delivery efficacy to target lung tumors while minimizing drug deposition on healthy tissues. Improved drug delivery will reduce unexpected side-effects and overall health care costs. Electronic cigarettes (ECs) show the possibility to be employed as the ready-made prototype of a next-generation device with built-in design advantages for targeted pulmonary drug delivery. Compared with existing drug inhalers, ECs have the following built-in advantages: (1) low inspiratory flow rate to trigger a 100% dose delivery (2.25 L/min), (2) flexible mouthpiece configuration design, and (3) wide choices of drug formulations. The above advantages provide physicians full control of the “air-drug stream” in human respiratory tracts to direct the drugs to the specific sites. As part of the preclinical study, it is important to evaluate the feasibility and effectiveness of the new methodology. Compared to experimental investigations, an accurate and realistic computer simulation model, i.e., a Computational Fluid-Particle Dynamics (CFPD) model governed by natural laws of physics would significantly contribute to reducing the research time and cost, and visualize drug-aerosol transport and deposition patterns with high resolution to advance the fundamental understanding of the underlying physics.

2. Research Objective

Motivated by the in-house preliminary studies and the potential benefits of EC, the primary research objective of this study is to investigate the validity and generality of the new inhalation therapy using EC technologies, and identify the optimal operational conditions for targeted drug delivery to treat lung cancers on a patient-specific level. Integrating the advantages of EC product design and CFPD modeling, a computer-aided targeted drug methodology and protocol is created to precisely control the drug trajectories in the human respiratory tract. Ideally, an individual’s CT-scan of his/her lung morphology and diseased site are known a priori, and the optimal drug targeting operation can be predicted with the CFPD simulations of drug particle transport and deposition for each individual.

3. Numerical Setup

ANSYS CFX and Fluent 18.0 were employed for the CFPD simulations. A Virtual Human (VH v1.0) was created to restore the realistic drug inhalation scenario. Three human upper airways were selected for the inter-subject variability study to validate the general feasibility of the targeted drug delivery method. Each human upper airway configuration contains an oral cavity, pharynx, larynx, and the same tracheobronchial tree. Inlet centers are all located at (x,y,z)=(0,0,0), and the gravity is along the positive x-direction. Realistic physical properties of pulmonary drug particles treating lung cancers were employed. Specifically, the particle diameter d_p is from 1 to 5 micron, and the particle density ρ_p is 1000 kg/m³. The inhalation flow rate Q_in varies from 2 to 10 L/min. The Euler-Lagrange scheme enhanced by in-house C programs was employed to simulate airflow and drug particle transport and deposition.

4. Results and Discussion

An experimental validated CFPD model was used to simulate drug particle transport and deposition in the three subject-specific human upper airway models with different geometric and operational parameters. These parameters include nozzle diameter, drug releasing velocity, drug releasing angle, EC-like inhaler position, and angle to oral cavity centerline, and breathing patterns. The general feasibility of the deeper lung tumor targeting methodology was validated. The optimal geometric and operational parameters for the new inhaler design were also determined to achieve the most effective targeting performance. A “drug particle release map” was generated for each case to correlate specific targeting site with a specific drug release position by a “backtracking” strategy. Specifically, the drug particle release maps were generated by backtracking the drug trajectories to link their release positions with their deposition locations using the high-resolution data provided by CFPD simulations. It can be observed from the parametric analyses that lower inhalation flow rate is preferred to guarantee the more regulated laminar flow regimes, which is easier for doctors to direct the air-drug streams to a specific site with minimum disturbance by the airflow fluctuation. Furthermore, the high morphological complexity of the human respiratory tract will generate more airflow fluctuation, thereby reducing the drug targeting effectiveness.

5. Summary

This study validated the general feasibility of the “controlled air-drug stream” method to target lung tumors by confirming the significant improvement of drug delivery efficiency at specific sites of lesions. Furthermore, the simulation process paves the way of a new protocol to seek personalized lung cancer treatment on a patient-specific level aided by CFPD simulations. Improved drug delivery will reduce unexpected side-effects and overall health care costs. The proposed research will provide non-invasive high-resolution data for patient-specific drug transport and deposition, a critical step towards translational work needed to maximize the efficiency of animal studies, to develop animal-to-human transfer functions, and to test development in clinical trials. This work is expected to support wider applications for creating new targeting strategies using EC product designs as the next-generation drug delivery device in combating a broad range of lung and systemic diseases.

6. Acknowledgements

The authors are grateful for the financial support by NIH (No. P20GM103648), and the use of ANSYS Software (ANSYS Inc., Canonsburg, PA) as part of the OSU-ANSYS Academic Partnership.