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Influence of Drug/Lipid Interaction on the Entrapment Efficiency Of Influence of drug/lipid interaction on the entrapment efficiency of isoniazid in liposomes for antitubercular therapy: a multi-faced investigation. Francesca Sciolla CNR-ISC Sede Sapienza, Piazzale A. Moro 2, I-00185 - Rome (Italy) 1, Domenico Truzzolillo ∗, Edouard Chauveau Laboratoire Charles Coulomb (L2C), University of Montpellier, CNRS, Montpellier, (France) Silvia Trabalzini Dipartimento di Chimica e Tecnologie farmaceutiche, Università di Roma, Piazzale A. Moro 5, I-00185 - Rome (Italy) Luisa Di Marzio Dipartimento di Farmacia, Università G.d’Annunzio, Via dei Vestini, 66100 - Chieti, (Italy) Maria Carafa, Carlotta Marianecci Dipartimento di Chimica e Tecnologie farmaceutiche La Sapienza Università di Roma, Piazzale A. Moro 2, I-00185 - Rome (Italy) 2, Angelo Sarra, Federico Bordi, Simona Sennato ∗ CNR-ISC Sede Sapienza and Dipartimento di Fisica, La Sapienza Università di Roma, Piazzale A. Moro 2, I-00185 - Rome (Italy) Abstract Hypothesis. Isoniazid is one of the primary drugs used in tuberculosis treatment. Isoniazid encapsulation in liposomal vesicles can improve drug therapeutic index and minimize toxic and side effects. In this work, we consider mixtures of hydrogenated soy phosphatidyl- choline/phosphatidylglycerol (HSPC/DPPG) to get novel biocompatible liposomes for isoniazid pulmonary delivery. Our goal is to understand if the entrapped drug affects bilayer structure. Experiments. HSPC-DPPG unilamellar liposomes are prepared and characterized by dynamic light scattering, ζ-potential, fluorescence anisotropy and Transmission Electron Microscopy. Isoniazid encapsulation is determined by UV and Laser Transmission Spec- troscopy. Calorimetry, light scattering and Surface Pressure measurements are used to get insight on adsorption and thermodynamic properties of lipid bilayers in the presence of the drug. Findings. We find that INH-lipid interaction can increase the entrapment capability of the carrier due to isoniazid adsorption. The pref- erential INH-HSPC dipole-dipole interaction promotes modification of lipid packing and ordering and favors the condensation of a HSPC-richer phase in molar excess of DPPG. Our findings highlight the importance of fundamental investigations of drug-lipid interactions for the optimal design of liposomal nanocarriers. arXiv:2101.10900v1 [cond-mat.soft] 26 Jan 2021 Keywords: unilamellar liposomes, isoniazid, drug-lipid interaction, laser transmission spectroscopy, calorimetry, scattering techniques 1. Introduction ∗Corresponding author Tuberculosis (TB) is caused by Mycobacterium tuberculo- 1 Laboratoire Charles Coulomb - UMR 5221, Universitè de Montpellier et sis (MTB), a bacterium that most often affects the lungs. The CNRS, Place E. Bataillon, Campus Triolet, Batiment 11, cc 0026 34095 Mont- pellier Cedex 05, (France) [email protected] di Roma, Piazzale A. Moro 2, I-00185 - Rome (Italy), +39 06 49913503, 2CNR ISC Sede Sapienza, Dipartimento di Fisica, La Sapienza Università [email protected] Preprint submitted to Elsevier January 27, 2021 World Health Organization estimates that about one-quarter of tilamellar nature of liposomes. Because of the increasing en- the world’s population has active or latent TB, and that a total capsulation capability of an hydrophilic drug with increasing of 1.5 million people died from TB in 2019 [1]. The current volume of the aqueous compartment of multilamellar vesicle, TB-treatment is usually associated with serious adverse effects, this system has been largely investigated. A further boost to resulting in poor compliance, which is one of the main reasons the use of multilamellar vesicles has been given by the possi- for the appearance of multidrug resistant strains and treatment’s bility to co-encapsulate two anti-TB drugs as rifampicin and failure [2]. Actually, encapsulation of anti-TB drug in nanocar- INH. The lipophilic rifampicin can be entrapped in the bilay- riers might be the modern answer for the development of in- ers enclosing adjacent aqueous compartments, where INH is novative anti-TB strategies. Nanocarriers can improve the effi- dispersed [13, 17]. Moreover, since the penetration depth of li- cacy of the current TB treatments since they can be function- posomes administered to the lungs through inhalation depends alized to bind MTB-infected phagocites via biological ligands, on the size of the particles in the aerosol, and particles with di- and used for inhalation administration, or to enhance drug load- ameters ranging from 0.1 to 2 µm can be effectively transported ing and pharmacokinetics, increasing significantly intracellular to the alveoli [5, 14], multilamellar vesicles are still under con- drug concentration. Since earlier studies proving a macropha- sideration. ge-specific delivery of anti-TB drugs [3, 4], liposomal vesicles However, despite all the aforementioned advantages offered still remain the most widely studied carrier system for anti-TB by multilamellar structures, these are far from being ideal car- drugs. Moreover, the possibility to nebulize of the liposomal riers from a biotechnological point of view, since their size and dispersion directly into the lungs offers a powerful route to over- the number of their compartments cannot be controlled at will, come the several limitations of oral and intravenous administra- raising precise regulatory issues [18]. For this reason, the devel- tion of anti-TB drugs [5]. opment of optimal unilamellar liposomal vectors, able to entrap Isoniazid (INH, pyridine-4-carbohydrazide) is one of the hydrophilic drugs, is highly desirable and still represents an im- primary drugs used in the TB treatment and is also well-known portant goal. for its value in preventive therapy [6]. Being a small hydrophilic Interestingly, since the earliest studies, it was argued that molecule, INH is generally entrapped in liposomes by using the the presence of a charged lipid could have a significant im- film hydration method [7] which leads to drug loading and re- pact on the entrapment efficiency. Wasserman and coworkers tention in liposomes due to the very small drug partition co- [19] showed that the addition of a low content of the anionic efficient [8, 9]. In general, the amount of a drug that can be Cardiolipin in a PC:Chol formulation yields a more efficient entrapped in a liposome is difficult to predict, since it may de- INH liposomal loading, possibly due to a minimum of the bi- pend on preparation method, physico-chemical properties of the layer permeability at an optimal PC:Cardiolipin stoichiometric carrier (such as lipid composition, geometry and size) and on ratio [20, 21]. Conversely, increasing cardiolipin molar fraction ionic force and pH of dispersing medium. Actually, for any decreases vesicle stability [19]. Since the Wasserman’s study solvophilic drug, including hydrophilic ones, due to the small dealt with multilamellar vesicles, the efficient loading found volume ratio between the internal volume of liposomes and at low molar fraction of charged lipid has been explained by that of the external medium, only a small amount of the drug arguing that negatively charged bilayers produce wider aque- molecules are encapsulated within the vesicles. ous spaces between lamellae, so to increase the volume of the Several attempts have been described to entrap INH in li- aqueous compartments available for INH entrapment. Also, in posomes with high efficiency, and since the first investigations anionic multilamellar liposomes containing DPPG and HSPC lipid composition has been recognized to be an important fac- lipids, a small amount of the anionic DPPG is able to confer tor regulating drug loading, as well as the accumulation of li- stability to the vesicles, without interfering with the encapsula- posomes in the lungs [10]. It has been shown that adminis- tion and retainment of a model drug during nebulization [22]. tration of sub-therapeutic INH doses entrapped in stealth lipo- To improve mucoadhesion and nebulization performances of li- somes composed by a mixture of phosphatidylcoline-pegylated posomal nanocarriers for pulmonary administration of drugs, a distearoylphosphatidylethanolamine-cholesterol (PC-DSPE-PEG- strategy based on polymer coating has been explored [23, 24]. Chol) with the anionic dicetilphosphate (DCP), is more effec- Also in this case, the authors report on the role of vesicle charge tive and sanatory than higher concentrations of the free drug for optimizing the polymeric coating by electrostatic interaction [3, 11]. Later, several other liposomal formulations based on with the bilayer, the charge conferring further mechanical sta- DPPC, DSPC, EggPC, crude soy lecithin [12, 13, 14, 15, 15], bility to the liposomes during nebulization. dioleoylphosphatidylethanolamine (DOPE) and DSPE-PEG [16] Within this framework, we focus our investigation on charged have been used for the efficient loading of INH. It’s worth re- unilamellar vesicles formed by HSPC mixed with the anionic marking that all these investigations considered both multil- DPPG, which have not been explored as potential INH car- amellar and unilamellar liposomes and, being these two struc- rier so far. This formulation offers, at least, two advantages: i) tures very different, a rigorous comparison of the results is dif- HSPC is already employed in several approved liposomal drugs ficult, especially for what concerns the entrapment efficiency. [25] and ii) the addition of DPPG gives the further possibility of Still, some very general principles guiding the optimization exploiting polymeric chitosan coatings
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