Encapsulated doxorubicin crystals influence lysolipid temperature-sensitive liposomes release and therapeutic efficacy in vitro and in vivo

JOURNAL OF CONTROLLED RELEASE

卷:328

Article

Ruiz, Amalia¹  Ma, Guanglong¹  Seitsonen, Jani²  Pereira, Sara G. T.^1,3  Ruokolainen, Janne²  Al-Jamal, Wafa T.¹ 

[1] Queens Univ Belfast, Sch Pharm, Belfast BT9 7BL, Antrim, North Ireland

[2] Aalto Univ, Dept Appl Phys, Sch Sci, POB 15100, FI-00076 Aalto, Finland

[3] AstraZeneca, Adv Drug Delivery Grp, Pharmaceut Sci, Aaron Klug Bldg,Granta Pk, Cambridge CB21 6GH, England

关键词: Lysolipid temperature-sensitive liposomes;    Hyperthermia;    Drug release;    Cancer therapy;    Doxorubicin;    Remote loading;   

DOI  :  10.1016/j.jconrel.2020.09.032

来源: Elsevier

【 摘 要 】

Doxorubicin (DOX)-loaded lysolipid temperature-sensitive liposomes (LTSLs) are a promising stimuli-responsive drug delivery system that rapidly releases DOX in response to mild hyperthermia (HT). This study investigates the influence of loaded DOX crystals on the thermosensitivity of LTSLs and their therapeutic efficacy in vitro and in vivo. The properties of DOX crystals were manipulated using different remote loading methods (namely (NH4)(2)SO4, NH4-EDTA and MnSO4) and varying the lipid:DOX weight ratio during the loading step. Our results demonstrated that (NH4)(2)SO4 or NH4-EDTA remote loading methods had a comparable encapsulation efficiency (EE%) into LTSLs in contrast to the low DOX EE% obtained using the metal complexation method. Cryogenic transmission electron microscopy (cryo-TEM) revealed key differences in the nature of DOX crystals formed inside LTSLs based on the loading buffer or/and the lipid:DOX ratio used, resulting in different DOX release profiles in response to mild HT. The in vitro assessment of DOX release/uptake in CT26 and PC-3 cells revealed that the use of a high lipid:DOX ratio exhibited a fast and controlled release profile in combination with mild HT, which correlated well with their cytotoxicity studies. Similarly, in vivo DOX release, tumour growth inhibition and mice survival rates were influenced by the physicochemical properties of LTSLs payload. This study demonstrates, for the first time, that the characteristics of DOX crystals loaded into LTSLs, and their conformational rearrangement during HT, are important factors that impact the TSLs performance in vivo.

【 授权许可】

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