Micro/Nanocomposite Drug Delivery Systems for Targeting Lung Cancer

Abstract

Magnolol (Mag) is a hydroxylated biphenyl agent isolated from the root and bark of Magnolia officinalis andused in Chinese traditional medicine for the treatment of various diseases. It has antioxidant, anti-inflammatory and antibacterial activities. Recently, a number of studies have drawn attention to the anticancer properties of Mag as it induces apoptosis and inhibits proliferation. However, Mag is sparingly soluble in water with a log Pof 5.03 and an oral bioavailability of 4-9% as it undergoes excessive first pass metabolism. Pulmonary drug delivery systems represent a viable option for the site specific effective treatment of lung cancer provided that the developed delivery systems can overcome the powerful lung defense mechanisms. Hence, the main aim of this study was to develop passively lung targeted Mag loaded micro/nanocomposite delivery systems that can overcome the biological lung barriers. For this purpose, two techniques were used in preparing drug delivery systems and their suitability for pulmonary application had been studied. The first technique to develop camouflaged inhalable Mag loaded MP that can avoid the uptake by alveolar macrophages was spray drying.Electrospinning was the second technique investigated for the development of Mag loaded electrospun composite systems: nanofibers (NF) and nanoparticles (NP). NF can be used as a mat to be applied postsurgical intervention to localize the drug, prolong its action and increase the survival rate and NP with their known fast uptake by cancer cells to be delivered using a suitable inhalation device. In chapter 1, two types of MP were generated, Mag loaded chitosan MP (CS-MP) and Mag loaded CS/phospholipids (Mag-CS/PLP) hybrid MP using the spray drying technique. The results showed that Mag-CS-MP prepared with aspartic acid exhibited higher AE% compare to those prepared with acetic acid. With both Mag-EPC-3 and DSPC hybrid MP, decreasing Mag to CS/PLP loading ratio from (0.04:1:1) to (0.08:1:1) led to increase in the yield, AE% and enhanced the flowability of the SDP. On the other hand, decreasing Mag loading in Mag-DPPG-Na MP did not have any significant impact on yield and AE%. MP spray dried with PLP were wrinkled hollow non-agglomerated MP in contrast to Mag-CS-MP which exhibited spherical, agglomerated particles showing crystals and nano-pores on their surfaces. A sustained release was successfully obtained with CS/PLP hybrid MP compared with the fast release of the drug from Mag-CS-MP. The release rate depended on the type of lipid used: in case of CS/EPC-3 hybrid MP, Mag loading% affected the release rate. Using a twin stage impinge, the emitted fraction from all formulae (EF%) was found to approximate 100%. The respirable fraction and effective inhalation index (EI%) ranged from 53.89 to 64.79% and 71.57 to 78.85%, respectively. DSC thermograms and FT-IR spectra of plain and drug loaded formulae suggested the formation of a new hybrid matrix between CS and PLP with different intensity depending on the type of the PLP. All chosen Mag loaded MP showed high cytotoxicity comparable to the pure solubilized drug. The plain SDP were found safe with no signs of toxicity on the lung cancer cells. The spray drying technique nor the excipients chosen altered the cytotoxicity activity of Mag.