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The current work was carried out by the principles of quality-by-design approach to develop an optimized solid lipid nanoparticles (SLNs) formulation of diallyl disulfide (DADS) through systematic statistical study. And its antitumor activity of DADS was also evaluated on breast cancer cell lines. To understand the effect of formulation variables (critical parameters) on the responses (critical quality attributes) of SLN, a 3-factor, 3-level Box-Behnken design, was explored to predict the responses such as particle size (Y1) and % entrapment efficiency (EE) (Y2) when concentration of surfactant (X1), amount of lipid (X2), and volume of solvent (X3) were selected as independent variables. Particle size analysis revealed that all the batches were within the nanometer range. DADS was released from the SLN much more rapidly at pH 4.5 than at pH 7.4, which is a desirable characteristic for tumor-targeted drug delivery. The cytotoxicity, reactive oxygen species (ROS), determination revealed that the antitumor activity of DADS is enhanced with SLN compared to DADS-free drug, and apoptosis is the mechanism underlying the cytotoxicity. The present study indicated the remarkable potential of DADS-SLN in enhancing the anticancer effect of DADS in breast cancer cells in vitro.

Acetyl Cholinesterase (AChE) inhibitors such as Donepezil, Rivastigmine and Galantamine are approved by US-FDA as first line drugs to treat the cognitive symptoms of Alzheimer's disease (AD). Their beneficial effects are attributed to their ability to elevate endogenous acetylcholine (ACh) at the M 1 muscarinic receptor in the brain. However, their side effects such as nausea, vomiting, dizziness, insomnia, loss of appetite and altered heart rate are related to non-specific activation of M 2 -M 5 muscarinic subtypes in various tissues. It is logical, therefore, to develop agonists with M 1 receptor selectivity. Unfortunately, this is limited due to a high degree of orthosteric site homology among the receptor subtypes. In contrast, their allosteric sites are unique and, therefore, allow selective targeting using positive allosteric modulators (PAMs). PAMs of M 1 receptors are devoid of agonist activity, however, when bound they enhance the binding affinity of orthosteric ligand, ACh. The major limitation of these PAMs is their bioavailability in the brain. In the current hypothesis, we propose surface modified nano-lipid drug conjugates (LDC-NPs) of PAMs of M 1 receptors to improve their bioavailability in brain. When co-administered with AChE inhibitors they are expected to increase their efficacy and reduce their therapeutic dose and side effects., (Copyright © 2017 Elsevier Ltd. All rights reserved.)