Evaluation of the physicochemical properties and the heat-triggered payload release from thermosensitive cationic liposomes formulated with a novel lipid
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Date
2022-07-13
Authors
Do Valle Moreira, Thales
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Abstract
Background: Heat-triggered local drug release rose as a promising strategy to treat localized diseases while reducing systemic off-target side effects. Thermosensitive liposomes (TSL) successfully exploit this targeting strategy, especially against solid tumors [1,2]. TSLs with negatively charged diglycerol-headed lipid have been described to allow sharp control drug release [3] and prolong circulation half-life (T½) without using polyethyleneglycol (PEG), avoiding related concerns [4]. Furthermore, a positive surface charge helps target cancerous cells and associated vasculatures [5] overexpressing negatively charged membrane-proteins and aberrant glycocalyx [6]. Objectives: the formulation of a novel diglycerol-functionalized ionizable cationic lipid (NICL) into cationic TSL (CTSL) was investigated. Here, the formulation screening of NICL-based CTSLs and their physicochemical characterization are thoroughly reported. Results: regardless of vesicle size (obtained by extrusion), zeta-potential (ZP) correlated with NICL mol%, resembling previously reported anionic TSL (ATSL) [4,5,7]. At pH 7.2, stable CTSL loaded with carboxyfluorescein (an anionic molecular marker; CF) could be formed with 10, 20, and 30 mol% NICL. Diluting the CTSL in buffers at different pHs immediately affected the ZP but not liposomal size, until the isoelectric points (pI) were reached (~pH 9), triggering aggregation. CF heattriggered release from CTSL was affected by the liposomal size and NICL mol%. Smaller liposomes with less NICL showed higher release rates. It correlated with the clearer phase-transition temperature (Tm) by differential scanning calorimetry (DSC). Conclusions: NICL can be formulated into CTSL similarly to previously published TSLs [4,5,7] with heat-responsiveness confirmed for a range of different formulations, the best at 10 mol% NICL and 50 nm. NICL-CTSLs behave as polyelectrolytes in aqueous media, with pKa ranging from 7.6 to 8.20 here.
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Keywords
Ionizable cationic lipid, Diglycerol, Thermosensitive liposomes, Formulation