Paclitaxel (PTX) being one of the most effective anticancer drugs, has been employed in treating lung cancer. It works by stabilizing the microtubules of cells and inhibiting the late G2 or M phases of the cell cycle, causing cells to die. However, PTX has poor aqueous solubility, limiting the clinical application. Although PTX has been formulated using Cremophor EL (brand name “Taxol”) consisting of castor oil and dehydrated ethanol to overcome solubility issues, it showed serious adverse effects such as allergic reactions. Solvent Cremophor EL also alters the drug kinetics, leading to non-linearity [1]. PTX also suffers from drug resistance due to P-gp efflux, which decreases the intracellular concentration of the drug. Therefore, the design of a novel formulation free of Cremophor EL is required to improve aqueous solubility and mitigate drug-related adverse effects.

Pulmonary nanomedicine has lately gained popularity towards treatment of lung cancer. Pulmonary route offer large surface area for absorption (∼100 m2), thin membrane for permeation (∼0.2 μm), limited proteolytic activity, low enzymatic action, and extensive absorption vascularization, make it an ideal route for drug administration [2], [3]. In addition, pulmonary nanomedicine reduces the drug inhomogeneity problem observed with aerosols of drug, alter drug solubility, and decrease mucociliary clearance and macrophage phagocytosis responsible for particle elimination of larger than 1 µm. Despite a lot of research to increase pulmonary nanomedicine deposition to lungs and increase drug bioavailability, a little progress has been achieved. Drug nanocrystals can be formulation of choice for pulmonary drug delivery owing to its sub-micron size, high payload, low excipient addition, high effective surface area, easy scale up feasibility, surface functionalization potential, and high stability towards aerosolization. Nanocrystals can be formulated as dry powder for inhalation (DPIs) and are freely flowing powder with excellent aerosolization performance responsible for homogenous particle distribution and deposition to deep lung to exert the therapeutic action [2]. Nanocrystals can either rapidly dissolve in lung fluid to release the free drug taken up by cells or can be taken up by cells in its intact form via clathrin-mediated and caveolae-mediated endocytosis pathways [4]. In addition, nanocrystals have the capability to interact with biological structures to facilitate mucoadhesion, drug permeation and cellular internalization [5]. Faster dissolution and higher permeation potential of nanocrystals results in a higher concentration gradient at site available for rapid diffusion to systemic circulation or cellular uptake. However, drug for exerting localized action in lung are required to retain there for a prolonged period. This can be achieved with nanocrystals by modifying its surface with phospholipids mimicking lung membrane (pulmonary surfactant and mucus layer) and thereby slowing drug release rate, minimizing lung clearance and prolonging drug retention [6], [7], [8].

In this study, we formulated a dry powder for inhalation of fucoidan stabilised and lipid-coated nanocrystals. Fucoidan (FP) are sulphated polysaccharide with high hydrophilicity, biodegradability, biocompatibility and drug delivery applications, thus employed as stabilizer for fabrication of nanocrystals of PTX as hydrophobic drug [9], [10]. Stabilization can be achieved through repulsion due to anionic fucoidan adsorbed on nanocrystals surface [11], [12]. Resultant nanocrystals (FPNCs) with high drug payload and hydrophilic surface can subsequently be coated with phospholipids to produce Lipo-NCs mimicking lung surface. Lipo-NCs acts as novel drug delivery system integrating drug nanocrystals into hydrophilic core of liposomes to form a hybrid system. Lipo-NCs offer advantage of both nanocrystals (high drug loading, enhanced dissolution, and improved aerosolization stability) as well as lipid-nanoparticles (colloidal stability, membrane fluidity, controlled drug release, and surface modification) [2], [13]. The Lipo-NCs can provide prolonged drug retention, lower drug clearance and high gradient concentration in lung [5], [7]. This can result in maximum drug localization in lungs available for uptake by lung cancer cells and also avoids drug distribution to other major organs, thereby providing better therapeutic effect and avoiding systemic side effects. Prepared nanocrystals were characterized for particle size, zeta potential, encapsulation efficiency, and drug loading. The nanocrystals were also characterized using various microscopy and spectroscopic techniques to confirm formation of fucoidan-stabilized amorphous nanocrystals and lipid-coated nanocrystals. In addition, wettability, saturation solubility, in-vitro drug release, in-vitro mucous diffusion, powder flow property, and aerosolization studies were conducted to determine their efficiency in drug delivery. Pharmacokinetic and biodistribution study were also done for confirming in-vivo performance and drug delivery potential of prepared nanocrystals.