title: Experimental design towards an optimal lipid nanosystem: a new opportunity for paclitaxel-based therapeutics.
abstract: Lipid based nanoparticles represent a class of nanocarriers that have caused great expectation, particularly due to their suitability to incorporate BCS class II and IV drugs. The use of solid lipid nanoparticles (SLNs) as a nanocarrier for antineoplastic agents has been underexplored when compared to the encapsulation of the same agents in polymeric particles. The preparation and efficacy assessment of a SLN platform as drug delivery carrier for anticancer agents, herein proposed as a strategy to find innovative formulations, could dramatically improve the outcome of cancer therapy. Considering these lipid nanoparticles, despite the great amount of insights described in the literature, it seems that improving their manufacturability could be the missing step to convert this system into a drug product. A way to circumvent that problem would be to select a preparation method that could take advantage of the pharmaceutical industry installed capabilities, thus speeding-up the scale-up translational steps while maintaining both regulatory compliance and flexibility. The High Pressure Homogenization (HPH) has proved to be a reliable process for SLN preparation. However, the use of the high-shear mixer, a well established process to manufacture coarse dispersions at industrial scale, has still not been fully explored to prepare SLN. In this study, we explore the possibility of using the hot emulsification/solidification method to prepare SLN's that complies with the current pharmaceutical quality requirements. Thus, a high-shear based process that consistently accomplishes performance requirements was optimized in order to standardize the nanocarrier production following the identification of some process and formulation critical parameters. A hydrophobic drug, Paclitaxel (Ptx) was successfully incorporated using the proposed developed method. The particles physicochemical characteristics changes caused by the drug entrapment as well as the particles stability were also evaluated. In addition the ability of SLN to travel across biological barriers due to its matrix lipid nature was explored upon comparing the efficacy of the drug loaded SLN with the conventional marketed drug product (Taxol®). The cellular uptake studies showed that the developed Ptx loaded SLN were in fact internalized and demonstrated higher efficacy in the cancer cells death process than Taxol. The experimental data demonstrated that the hot homogenization technique using a high-shear mechanical homogenizer allows the preparation of suitable size (around 150 nm) SLN. Overall, the results obtained can be particularly impactful in the forthcoming SLN research.
authors.affiliation: iMed.UL, Research Institute for Medicines and Pharmaceutical Sciences, Faculty of Pharmacy, University of Lisbon, Av. Professor Gama Pinto, 1649-003 Lisbon, Portugal. mvideira@ff.ul.pt
authors.forename: Mafalda A
authors.initials: MA
authors.lastname: Videira
authors.forename: Alexandra G
authors.initials: AG
authors.lastname: Arranja
authors.forename: Luís F
authors.initials: LF
authors.lastname: Gouveia
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004075:Diglycerides / Q000737:chemistry; D005227:Fatty Acids / Q000737:chemistry; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D017239:Paclitaxel / Q000008:administration & dosage / Q000737:chemistry*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004075:Diglycerides; D005227:Fatty Acids; C086409:glyceryl behenate; C009032:precirol; D017239:Paclitaxel