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.
