Intratracheal Administration of pH-Responsive Nanomicelles: A More Effective Strategy for Enhanced Intracellular Drug Delivery in Lung Cancer Treatment

Background: The efficacy of chemotherapy for treating lung cancer is hindered by insufficient intracellular drug utilisation. Moreover, non-targeted distribution often leads to severe side effects, resulting in poor prognosis and low patient compliance. Therefore, a more effective strategy is required to achieve effective treatment. In this study, we aimed to develop a pH-responsive nanoplatform for intratracheal administration to enhance drug accumulation in lung cancer tissues and promote the accumulation of drugs within tumour cells. Results: A self-assembled nanomicelle named SN-38@PEG-PMMSD (PPM) was constructed using a cinnamaldehyde synthetic carrier material loaded with SN-38 and nanoprecipitation. Intratracheal administration enhanced the accumulation of PPM within the lungs and tumors (the fold increase in lung accumulation following intratracheal (i.t.) were 49.63-fold higher than intravenous (i.v.) delivery at the 48-hour timepoint). Owing to its small size, PPM can easily penetrate deep into tumour tissues. The micro-acidic environment characteristic of tumours increases the efficiency of tumour cell uptake of PPM. This triggered a pH-responsive reaction in the acidic lysosomal milieu, leading to dissociation of PPM and the regeneration of cinnamaldehyde while releasing SN-38. Cinnamaldehyde acted as a reactive oxygen species (ROS) amplifier, facilitating ROS generation. Elevated ROS levels, in conjunction with SN-38, resulted in strong antitumor effects. Conclusion: In summary, Intratracheal administration of pH-responsive PPM is anticipated to enhance drug accumulation in tumour tissues, improve drug uptake by tumour cells, and achieve effective treatment of lung cancer.