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. 2021 Apr 7:16:2667-2687.
doi: 10.2147/IJN.S306831. eCollection 2021.

Design and Characterization of Spray-Dried Proliposomes for the Pulmonary Delivery of Curcumin

Islam M Adel  1 , Mohamed F ElMeligy  1 , Mohamed E A Abdelrahim  2 , Amr Maged  3   4 , AbdelFattah A Abdelkhalek  5 , Azza M M Abdelmoteleb  6 , Nermeen A Elkasabgy  1
Affiliations

Design and Characterization of Spray-Dried Proliposomes for the Pulmonary Delivery of Curcumin

Islam M Adel et al. Int J Nanomedicine. .

Abstract

Purpose: The goal was to directly deliver curcumin, a natural polyphenolic anticancer and anti-inflammatory compound, to the lung tissues with minimal systemic exposure through the fabrication of proliposomes, overcoming its poor aqueous solubility and oral bioavailability.

Methods: Nano-spray drying was employed to prepare proliposomes using hydroxypropyl beta-cyclodextrin as a carrier. Lecithin and cholesterol were used as lipids, stearylamine and Poloxamer 188 were added as positive charge inducer and a surfactant, respectively. Different characterization parameters were evaluated like percentage yield, entrapment efficiency, drug loading, aerodynamic particle size, in vitro release besides morphological examination. Cytotoxicity studies on cell line A549 lung tumor cells as well as in vivo lung pharmacokinetic studies were also carried.

Results: The optimized formulations showed superior aerosolization properties coupled their enhanced ability to reach deep lung tissues with a high % of fine particle fraction. Cytotoxicity studies using MTT assay demonstrated enhanced growth inhibitory effect on lung tumor cells A549 and significant reduction of proinflammatory cytokines such as tumor necrosis factor-α, interleukin-6 and interleukin-10 compared to the pure drug. Results of lung pharmacokinetic tests confirmed the superiority of proliposomal curcumin over curcumin powder in both, the rate and extent of lung tissue absorption, as well as the mean residence time within the lung tissues.

Conclusion: The pulmonary delivery of curcumin-loaded proliposomes as dry powder provides a direct approach to lung tissues targeting while avoiding the limitations of the oral route and offering a non-invasive alternative to the parenteral one.

Keywords: curcumin; cyclodextrin; dry powder inhalers; human epithelial cell line; proliposomes; pulmonary delivery.

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Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Steps of the surgical procedure of curcumin administration to a male Albino rat. (A) Syringe is prepared then (B) Endotracheal intubation of SD/P formulation (or free curcumin) in the rat. (C) At predefined time intervals, a rat is sacrificed and (D) lung tissue is isolated. (E) Later, prior to analysis, lung tissue is homogenized.
Figure 2
Figure 2
Curcumin release profiles from spray-dried proliposomes formulations (SD/P) in ethanolic phosphate buffer solution (30% v/v; pH 7.4). The release profile of all the investigated formulations showed a distinctive biphasic release profile, where nearly more than 17.00% and less than 24.98% curcumin were released during the first 2 h followed by a sustained release pattern during the 48h testing period. All formulations released more than 95% curcumin at Q24h. No significant difference could be detected between investigated formulations in either Q2h or Q24h (P > 0.05).
Figure 3
Figure 3
Curcumin amounts trapped (A) within the pre-separator and USP throat and (B) on each stage of the Andersen cascade impactor, respectively. The total amount of the improved SD/P4 trapped within both the pre-separator and USP throat was significantly lower than that of either the improved SD/P6 or the free curcumin (P < 0.05). The total amount of the improved SD/P4 reaching deeper stages of the Andersen cascade impactor was significantly higher than that of the improved SD/P6 (P < 0.05) with much superiority of the improved SD/P6 over free curcumin (P < 0.05).
Figure 4
Figure 4
FT-IR spectra of (A) curcumin, (B) lecithin, (C) cholesterol, (D) SA, (E) PLX 188, (F) HPβCYD, (G) SD/P4 improved physical mixture, (H) SD/P6 improved physical mixture, (I) improved SD/P4 formulation and (J) improved SD/P6 formulation. The characteristic peak of curcumin completely disappeared in the spectra of the improved SD/P formulations with the shift of HPβCD peak to a lower wavelength (I and J) are suggestive of possible formation of inclusion complex of curcumin in HPβCD.
Figure 5
Figure 5
DSC thermograms of (a) curcumin, (b) lecithin, (c) cholesterol, (d) SA, (e) PLX 188, (f) HPβCYD, (g) SD/P4 improved physical mixture, (h) SD/P6 improved physical mixture, (i) improved SD/P4 formulation and (j) improved SD/P6 formulation. The characteristic endothermic peak of curcumin completely disappeared in the DSC thermograms of the improved SD/P formulations with the shift of the endothermic peak of HPβCD to a lower temperature coupled with a decrease in its intensity, all of which is suggestive of possible interaction and complexation of curcumin in HPβCD (i and j).
Figure 6
Figure 6
TEM images of the improved (A) SD/P4 and (B) SD/P6. Both formulations showed spherical liposomes.
Figure 7
Figure 7
SEM images of the improved (A) SD/P4 and (B) SD/P6. Both formulations showed hollow-shaped spherical particles.
Figure 8
Figure 8
Effect of curcumin powder, medicated improved formulations and non-medicated improved formulations on (A) the growth of A549 tumor cells and (B) the levels of TNF-α, IL-6 and IL-10 as measured in A549 tumor cells. The growth inhibitory effect of the improved formulations was significantly higher (P < 0.05) than that of the free curcumin (A). Also, the improved formulations were significantly more potent (P < 0.05) at lowering the levels of the pro-inflammatory cytokines as compared to the free curcumin (B).
Figure 9
Figure 9
Lung concentration–time curve for curcumin-free powder and curcumin proliposomal formulations. The improved formulations exhibited shorter Tmax, higher Cmax, AUC(0–24) and AUC(inf) values compared to the free curcumin powder (P < 0.05). This suggests an enhancement in both the rate and extent of the improved formulation uptake by lung tissues as compared to the free curcumin.
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