Physicochemical characterization of asulacrine towards the development of an anticancer liposomal formulation via active drug loading: Stability, solubility, lipophilicity and ionization

International Journal of Pharmaceutics

Falconer

Baguley

et al. 2016

Self Cite

This paper describes a novel method to improve drug retention in liposomes for the poorly water-soluble (lipophilic) model drug asulacrine (ASL). ASL was loaded in the aqueous phase of liposomes and the effects of aging conditions and drug loading levels on drug retention were investigated using an in vitro bio-relevant drug release test established in this study. The status of intra-liposomal drug was investigated using differential scanning calorimetry (DSC) and cryo-transmission electron microscopy (cryo-TEM). Pharmacokinetics and venous tolerance of the formulations were simultaneously studied in rabbits following one-hour intravenous infusion via the ear vein. The presence of glucose during aging was found to be crucial to accelerate drug precipitation and to stabilize the liposomal membrane with high drug loading (8.9% over 4.5% w/w) as a prerequisite. Although no drug crystals were detected, DSC showed a lower phase-transition peak in the glucose-assisted aged ASL-liposomes, indicating interaction of phospholipids with the sugar. Cryo-TEM revealed more 'coffee bean' like drug precipitate in the ASL-liposomes aged in the glucose solution. In rabbits, these liposomes gave rise to a 1.9 times longer half-life than the fresh liposomes, with no venous irritation observed. Inducing and stabilizing drug precipitation in the liposome cores by aging in the presence of sugar provided an easy approach to improve drug retention in liposomes. The study also highlighted the importance of bio-relevance of in vitro release methods to predict in vivo drug release.

Section: Introductionmentioning

confidence: 88%

Section: Establishment Of a Bio-relevant Release Study Methodsmentioning

confidence: 99%

Section: Pharmacokinetics In Rabbitsmentioning

confidence: 99%

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Improving drug retention in liposomes by aging with the aid of glucose

International Journal of Pharmaceutics

Falconer

Baguley

et al. 2016

Self Cite

“…ASL was administered intravenously as an isethionate salt, which is lipophilic (log P value ≈ 3.0 at pH 7) and moderately soluble in water (the solubility is ∼1 mg/mL, pH is ∼4.5; See et al., 2014 ). Our previous studies showed that post-injection drug precipitation upon dilution of body fluid and drug irritancy were probably the main reasons for phlebitis with ASL (See et al., 2014 ; Zhang et al., 2015a ). Different strategies using liposome carriers have been attempted to improve phlebitis caused by ASL (Zhang et al., 2015a , b , 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Multiseed liposomal drug delivery system using micelle gradient as driving force to improve amphiphilic drug retention and its anti-tumor efficacy

et al. 2018

Drug Delivery

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To improve drug retention in carriers for amphiphilic asulacrine (ASL), a novel active loading method using micelle gradient was developed to fabricate the ASL-loaded multiseed liposomes (ASL-ML). The empty ML were prepared by hydrating a thin film with empty micelles. Then the micelles in liposomal compartment acting as ‘micelle pool’ drove the drug to be loaded after the outer micelles were removed. Some reasoning studies including critical micelle concentration (CMC) determination, influencing factors tests on entrapment efficiency (EE), structure visualization, and drug release were carried out to explore the mechanism of active loading, ASL location, and the structure of ASL-ML. Comparisons were made between pre-loading and active loading method. Finally, the extended drug retention capacity of ML was evaluated through pharmacokinetic, drug tissue irritancy, and in vivo anti-tumor activity studies. Comprehensive results from fluorescent and transmission electron microscope (TEM) observation, encapsulation efficiency (EE) comparison, and release studies demonstrated the formation of ML-shell structure for ASL-ML without inter-carrier fusion. The location of drug mainly in inner micelles as well as the superiority of post-loading to the pre-loading method , in which drug in micelles shifted onto the bilayer membrane was an additional positive of this delivery system. It was observed that the drug amphiphilicity and interaction of micelles with drug were the two prerequisites for this active loading method. The extended retention capacity of ML has been verified through the prolonged half-life, reduced paw-lick responses in rats, and enhanced tumor inhibition in model mice. In conclusion, ASL-ML prepared by active loading method can effectively load drug into micelles with expected structure and improve drug retention.

“…Marchetti 2014), such as Poloxamer 188 (P188) modified ASL-loaded long-circulating liposomes, which had a prolonged half-life but no drug precipitation compared with ASL solution (See, Zhang, Liu, Svirskis, Baguley, Shaw, Wang andWu 2014, Zhang, Wang, See, Shaw, Baguley, Liu, Amirapu andWu 2015). This way, ASL-liposome may act as an alternative formulation to prevent phlebitis during i.v.…”

Section: Introductionmentioning

confidence: 99%

Quantitative determination of intracellular Asulacrine in MCF‐7 breast cancer cells by liquid chromatography–mass spectrometry and its application to cellular pharmacokinetic studies of P188 modified liposomes

Zang

Biomedical Chromatography

Zhou

et al. 2016

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Asulacrine (ASL), an analogue of amsacrine, has shown higher anti-breast and anti-lung cancer activity. Hereby, a new sensitive and selective liquid chromatography-mass spectrometry (LC/MS) method was developed to determine intracellular asulacrine. The chromatographic separation was performed on an Agilent Zorbax Extend-C column (2.1 mm i.d. × 50 mm, 5 μm) using gradient elution with water (2 mmol/L ammonium acetate and 0.1% acetic acid) and acetonitrile as the mobile phase. The detection was achieved with selected ion monitoring mode using electrospray ionization in positive mode with target ions at m/z 465.3 and m/z 326.1 for asulacrine and midazolam, respectively. The standard curve showed a good linearity with the lower limit of quantification of 1 ng/mL, as a result of which, the trace concentration of ASL in cell suspension could be quantified. The intra- and inter-day accuracy ranged from -5.28 to 6.5% and from -6.32 to 1.05%, and the intra- and inter-day precisions were no more than 7.65% and 11.71%, respectively. Additionally, no degradation of asulacrine was observed during stability evaluation. The method was proved to be powerful and practical to determine and compare the intracellular distribution and kinetics of ASL under different formulations in MCF-7 breast cancer cells.