Periodic Reporting for period 1 - AEROTARG (Focused Targeting of Inhaled Magnetic Aerosols for Lung Cancer)
Periodo di rendicontazione: 2023-06-01 al 2024-11-30
Lung cancer is still the number one leading cause worldwide of deaths from cancer, both in males and females. Lung cancer is roughly divided into non-small cell lung cancer (~85%) and small cell lung cancer (~15%). Notably, (non-small) squamous cell carcinomas is one of the most aggressive forms of cancer with ~2M patients/year and holds very low survival rates with each increasing cancer stage. Ongoing mortality outcomes call for urgent developments of new drug delivery modalities. One of the big drawbacks of systemic chemotherapy is captured in low doses of active drugs that reach cancerous cells (i.e. typical uptake: ~1% in the entire lungs), thereby causing debilitating side effects. These impose administering suboptimal doses responsible in part for poor treatment outcomes. In some instances, brachytherapy may be used to treat a tumor locally. Yet, the method is limited to the first few airway generations, while smaller bronchi remain beyond reach. There has been tremendous progression in the treatment of non-small lung cancer over the last decade with the initiation of immunotherapies, while for small-cell lung cancer immunotherapy has largely failed, with little change in the overall course of the disease that is fatal with short prognostics (~5 yr survival rate is ~2%, with median of 1 year and max. 2 yr).
The index of proliferation small-cell lung cancer is very high, nearing ~100% (i.e. all cells in the tumor are dividing) and thus very aggressive. The tragedy lies in that 100% of small-cell lung cancer recurs for such patients within half a year to a year, by which time the cancer is not only unresponsive to the chemotherapy but also to radiation therapy. Currently, new chemotherapeutic agents are being evaluated but none have yet succeeded in addressing this “2nd stage” relapse in the cancer. Instead, our strategy is to administer a high concentration of chemotherapeutics in a manner that overcomes corresponding doses via systemic circulation that would otherwise be fatal to the patient. In a paradigm change in pulmonary drug delivery, our proposed inhaled aerosol targeting platform will enable the selective targeting to the tumour surroundings only.
Inhalation aerosols are a hallmark of respiratory therapy in treating pulmonary diseases (e.g. asthma, COPD). Yet, inhalation therapy is overwhelmingly absent in lung cancer treatment. With the enormous drawbacks of current systemic delivery, topical chemotherapy delivery has been explored with aerosol inhalation. Outcomes of clinical trials have shown some promising results, e.g. reduced systemic side effects, tolerable adverse effects in healthy pulmonary tissue and survival increase in phase II trials. Yet, as aerosolized drugs deposit rather indiscriminately in the lungs, whereas cancerous lesions/tumours are localized, lung toxicities still pose an important challenge with high drug doses depositing in undesired locations, thus coming short of offering tangible advantage over intravenous injection.
By incorporating magnetic agents into inhalable drugs8, notably Superparamagnetic Iron Oxide Nanoparticles (SPIONs), targeted lung deposition can be attained using external magnetic fields. From a toxicity standpoint, SPIONs are approved for clinical use as imaging contrast agents and can be combined with various therapeutics. While preclinical animal experiments support the prospect of increasing regional lung deposition9, the ability to target aerosols to a localized cancer tumors remains widely beyond reach with current drug delivery modalities.
The index of proliferation small-cell lung cancer is very high, nearing ~100% (i.e. all cells in the tumor are dividing) and thus very aggressive. The tragedy lies in that 100% of small-cell lung cancer recurs for such patients within half a year to a year, by which time the cancer is not only unresponsive to the chemotherapy but also to radiation therapy. Currently, new chemotherapeutic agents are being evaluated but none have yet succeeded in addressing this “2nd stage” relapse in the cancer. Instead, our strategy is to administer a high concentration of chemotherapeutics in a manner that overcomes corresponding doses via systemic circulation that would otherwise be fatal to the patient. In a paradigm change in pulmonary drug delivery, our proposed inhaled aerosol targeting platform will enable the selective targeting to the tumour surroundings only.
Inhalation aerosols are a hallmark of respiratory therapy in treating pulmonary diseases (e.g. asthma, COPD). Yet, inhalation therapy is overwhelmingly absent in lung cancer treatment. With the enormous drawbacks of current systemic delivery, topical chemotherapy delivery has been explored with aerosol inhalation. Outcomes of clinical trials have shown some promising results, e.g. reduced systemic side effects, tolerable adverse effects in healthy pulmonary tissue and survival increase in phase II trials. Yet, as aerosolized drugs deposit rather indiscriminately in the lungs, whereas cancerous lesions/tumours are localized, lung toxicities still pose an important challenge with high drug doses depositing in undesired locations, thus coming short of offering tangible advantage over intravenous injection.
By incorporating magnetic agents into inhalable drugs8, notably Superparamagnetic Iron Oxide Nanoparticles (SPIONs), targeted lung deposition can be attained using external magnetic fields. From a toxicity standpoint, SPIONs are approved for clinical use as imaging contrast agents and can be combined with various therapeutics. While preclinical animal experiments support the prospect of increasing regional lung deposition9, the ability to target aerosols to a localized cancer tumors remains widely beyond reach with current drug delivery modalities.
To directly tackle these shortcomings, we have identified the leading engineering hurdles prohibiting successful targeting of inhaled magnetic aerosols to an airway site. First, (i) aerodynamic drag forces are vastly larger than the magnetic force imposed by magnets on inhaled aerosols; in turn, deflecting aerosols during inhalation for targeted deposition has been limited. Concurrently, the targeting efficiency (i.e. ratio between number of aerosols on target vs rest) stands at only ~2-3 in preclinical studies. This follows as (ii) the magnetic field is always strongest near the magnet leading to undesired deposition in the lung space between target and magnet. Lastly, (iii) most inhalation aerosols (~1-5 µm diameter) are specifically intended to increase broad lung deposition. This strategy hampers any selective targeting ability, most notably as a result of gravitational deposition (i.e. sedimentation) for such particle size range.
To overcome these engineering limitations, our novel delivery modality revolves around a smart inhaler coupled with a ventilation machine and a custom-designed magnetic field. To minimize deposition of magnetic particles located in the airspace between the magnet and the target airway, the inhaler generates a short, pulsed bolus of SPION-laden aerosols, after which the ventilator tracks the volume of air pushed behind the bolus to reach the targeted site along the airway path. Unlike traditional inhalation, we confine aerosols to a tight bolus rather than a continuous stream, thus minimizing airborne particles located in the airways between the magnet and the target; this drastically reduces superfluous deposition in untargeted regions. Next, we implement a short breath-hold that annuls drag forces induced during breathing thereby augmenting the magnet’s ability to deflect and deposit aerosols. Critically, our inhaler delivers aerosols in the ~500 nm range that are exhaled under normal breathing due to weak diffusional or gravitational forces; such particles are widely considered a poor choice in inhalation therapy. Here, we specifically leverage this characteristic to dramatically increase the deposition ratio whereby aerosols located away from the magnetic field remain airborne throughout the protocol, and are thereafter exhaled.
Over the course of this PoC, we have worke on demonstrating in corresponding adult-sized lungs the technical capabilities of the targeted delivery modality. Equipped with the smart inhaler prototype coupled with the custom ventilation machine that tracks the flowrate inhaled and the total volume of air inhaled, we have been working on ex vivo experimental campaigns using porcine lungs. At this stage, we have had some promising preliminary results but the technique still needs considerable refinement and fine tuning to guarantee controlled and selective delivery of inhaled aerosols to a designated airway site. In the appendix, we illustrate in photographs some examples of the current setup and experiments running in the lab using porcine lungs, as well as the quantitative endpoints to measure deposition via fluorescent signalling.
To overcome these engineering limitations, our novel delivery modality revolves around a smart inhaler coupled with a ventilation machine and a custom-designed magnetic field. To minimize deposition of magnetic particles located in the airspace between the magnet and the target airway, the inhaler generates a short, pulsed bolus of SPION-laden aerosols, after which the ventilator tracks the volume of air pushed behind the bolus to reach the targeted site along the airway path. Unlike traditional inhalation, we confine aerosols to a tight bolus rather than a continuous stream, thus minimizing airborne particles located in the airways between the magnet and the target; this drastically reduces superfluous deposition in untargeted regions. Next, we implement a short breath-hold that annuls drag forces induced during breathing thereby augmenting the magnet’s ability to deflect and deposit aerosols. Critically, our inhaler delivers aerosols in the ~500 nm range that are exhaled under normal breathing due to weak diffusional or gravitational forces; such particles are widely considered a poor choice in inhalation therapy. Here, we specifically leverage this characteristic to dramatically increase the deposition ratio whereby aerosols located away from the magnetic field remain airborne throughout the protocol, and are thereafter exhaled.
Over the course of this PoC, we have worke on demonstrating in corresponding adult-sized lungs the technical capabilities of the targeted delivery modality. Equipped with the smart inhaler prototype coupled with the custom ventilation machine that tracks the flowrate inhaled and the total volume of air inhaled, we have been working on ex vivo experimental campaigns using porcine lungs. At this stage, we have had some promising preliminary results but the technique still needs considerable refinement and fine tuning to guarantee controlled and selective delivery of inhaled aerosols to a designated airway site. In the appendix, we illustrate in photographs some examples of the current setup and experiments running in the lab using porcine lungs, as well as the quantitative endpoints to measure deposition via fluorescent signalling.
Ultimately, when we reach our ex vivo feasibility, we aim for a Phase I trial to assess the safety of administering the dual chemotherapy agents using our device. This first safety trial envisioned here at the Rambam Health Care Campus (Haifa) will allow to administer high doses of cytotoxic agents solely to the airway tumor environment, thus increasing the chemotherapy efficacy while decreasing the toxicity profile. At this time, and without Patent in place, we are still in the research phase, and it is still too soon to decide on aspects pertaining commercialization, IPR support, internationalization, supportive regulatory and standardization framework.