Jiang, Chengwei; (2025) Design and Development of Inhalable Nanoformulations of Phytochemicals for the Management of Pulmonary Conditions. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Pulmonary fibrosis and non-small cell lung cancer (NSCLC) remain significant global health concerns due to limited treatment efficacy, drug resistance, and adverse side effects. While natural compounds like icariin (ICA) and curcumin (CUR) exhibit therapeutic potential, their clinical use is hampered by poor water solubility and bioavailability. This study addresses these limitations by developing inhalable nanocarrier formulations for targeted pulmonary delivery. We initially screened various amphiphilic agents, including TPGS, Soluplus®, Kolliphor® HS15, DSPE-PEG2000, and DPPC, for their ability to encapsulate ICA. Among these, ICA/TPGS micelles demonstrated the highest encapsulation efficiency (85%) and drug loading capacity (8%). Building on these findings, a TPGS/DPPC formulation co-encapsulating ICA and CUR was optimized for lung cancer treatment. The resulting CUR+ICA/TPGS/DPPC micelles (1:1:9:1, w/w/w/w) demonstrated a small particle size (18nm), high drug loading (18%), nearly 90% encapsulation efficiency for both drugs, and a near-neutral zeta potential. The optimized formulations demonstrated enhanced cytotoxicity against A549 lung cancer cells, achieving an IC50 value (3 μg/mL) significantly lower than doxorubicin (30 μg/mL). Additionally, the micelles exhibited potent antioxidant properties (IC50 = 39 μg/mL), supporting their role in oxidative stress reduction . Aerosolization studies indicated a fine particle fraction of 67 ± 3% and an emitted fraction of 95 ± 0%, suggesting efficient pulmonary deposition. For pulmonary fibrosis management, two ICA-loaded formulations, micelles in aqueous suspension (for nebulization) and a spray-dried powder were developed. ICA/DSPE-PEG2000/DPPC (15:70:30, w/w/w) micelles exhibited a high encapsulation efficiency (~95%), elevated drug loading (~12%), and small particle size (~10nm). NGI aerosolization studies showed a fine particle fraction of 63.5 ± 4%, indicating that most of the nebulized micelles can reach deep lung alveoli. The micelles displayed an IC50 of 29 ± 3 μg/mL against A549 cells, with robust cellular uptake confirmed by fluorescence microscopy and flow cytometry. Using spray drying at 150°C, we generated a free-flowing ICA/DSPE-PEG2000/DPPC powder of spherical particles (D50 = 2.36 μm) that retained excellent aerosol properties (emitted fraction 93%, fine particle fraction 44%) suitable for alveolar delivery. Cellular uptake studies on A549 and RAW 264.7 cells demonstrated enhanced micelle internalization versus free ICA. Notably, ICA-loaded micelles effectively inhibited M2 macrophage polarization, a key fibrotic mechanism, reducing CD206 and Arg1 expression. Confocal imaging and Simple Western analysis significant downregulation of these M2 markers, highlighting the antifibrotic potential of the formulation. This study establishes novel inhalable micellar systems for ICA and/or CUR, significantly enhancing their solubility and targeted pulmonary drug delivery. These formulations represent promising therapeutic strategies for pulmonary fibrosis and NSCLC, necessitating further in vivo validation and clinical translation to advance their potential clinical application.

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