# Chitosan-Coated Nanoparticles: Effect of Chitosan Molecular Weight on Nasal Transmucosal Delivery
## 1 Introduction  
Statins are potent inhibitors of the hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase, and they are commonly administered for the treatment of cardiovascular disease [1]. However, in recent years, it has been suggested that the statin therapeutic indications might expand, due to their pleiotropic effects [2]. These non-cholesterol-related effects include their modulation of immune responses, the enhancement of endothelial function, the reduction of oxidative stress, and checking of inflammation processes [3; 4]. The majority of pleiotropic effects are mediated by preventing the synthesis of isoprenoids, and the subsequent inhibition of small signaling proteins [5; 6]. Among the diseases that could benefit from statin's pleiotropic effects are multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, chronic obstructive pulmonary disease, neurodegenerative disorders, bacterial infections, and cancer [3]. In the field of cancer therapy, statins showed pro-apoptotic effects against various tumor cell lines [7; 8], and numerous studies have examined their potential chemopre active [9]. Due to the inhibition of the enzyme HMG-CoA reductase, statins decrease the levels of mevalonate, the precursor of dolichol, geranylpyrophosph (GPP), and farnesyl-pyrophosph (FPP). Dolichol enhances DNA synthesis and is associated with several proteins found in tumor cells [10]. GPP and FPP are post-translational modifications of intracellular proteins as the G-proteins Ras and Rho, which regulate the signal transduction of several membrane receptors, and which are critical for the transcription of genes involved in cell proliferation, differentiation, and apoptosis. Ras and Rho gene mutations are found in a variety of tumor cells [7; 11]. Furthermore, statins show apoptotic effects in human glioblastoma cell lines that induce the depletion of geranylgeranylated proteins, which is important for the transition to cell cycle phases [12]. statins have also shown to play a role in the prevention of tumor metastases by the inhibition of epithelial growth factor-induced tumor cell invasion [13]. Moreover, statins, inducing the inactivation of nuclear factor kB, reduce urokinase and matrix metalloproteinase-9 expression, which are pivotal for tumor metastatic processes [7; 14]. In the case of glioma cell lines, simvastatin (SVT) showed a suppression of cell proliferation and the induction of apoptosis [15; 16]. However, when evaluated in an in vivo orthotopic model of the glioblastoma multiform model, simvastatin did not show tumor-inhibitory effects [17]. As in this experiment, the major factor for the failure of chemotherapies against central nervous system (CNS) tumors has been attributed to limited brain-blood barrier (BBB) permeability [18]. In addition, after oral administration statins are extensively metabolized in the liver, their hydrophilic metabolites are prevented from crossing the BBB [19]. Some new strategies have been proposed to deal with such limitations in order to increase the distribution of drugs in the CNS, such as the use of nose-to-brain route [20; 21] and the development of nanocarriers [22; 23; 24]. In recent years, nose-to-brain delivery has attracted much attention as a means of delivering drugs more efficiently to the CNS bypassing the BBB. This is because the nasal cavity is anatomically connected to the CNS via the olfactory system [25]. Moreover, it offers advantages such as non-invasiveness, the avoidance of hepatic first-pass metabolism, practicality and the convenience of administration [26]. However, due to the presence of the rapid mucociliary clearance mechanism, nasal delivery applications for brain delivery are hindered by the short residence time of conventional formulations. Moreover, the barrier of the nasal epithelium, nasal metabolism, and the limited volume of administration are limiting aspects for the development of nose-to-brain drug delivery systems [25; 27].