Self-assembled squalenoyl-cytarabine nanostructures as a potent nanomedicine for treatment of leukemic diseases

Figures & data

Table 1 Physicochemical parameters of squalenoyl nanoaggregates*

Samples	Size (nm)	Polydispersity index	Zeta potential
Squalenoyl nanoassemblies	105.6 ± 12.7	0.08 ± 0.019	−24.8 ± 5.6
Sq-Ara-C nanomedicine	146.1 ± 6.7	0.09 ± 0.015	−26.5 ± 3.1

Note:

* Each value represents the average of three different experiments ± standard deviation.

Figure 1 Transmission electron micrograph of the Sq-Ara-C nanoaggregates (A). Interaction between [³H]CHE radiolabeled Sq-Ara-C and the different cancer cell lines (B). Confocal laser scanning micrograph (C), relative three-dimensional image (D) and 4× zoom (E) showing the interaction between MCF-7 cells and the fluorescein-DHPE-labeled Sq-Ara-C nanoaggregates after 3 hours of incubation.

Table 2 Evaluation of IC₅₀ (μM) of Ara-C and Sq-Ara-C in different cancer cell lines*

	24 hours		48 hours
	Ara-C	Sq-Ara-C	Ara-C	Sq-Ara-C
L1210	0.051 ± 0.012	0.027 ± 0.008	0.022 ± 0.003	0.017 ± 0.006
L1210R	71.7 ± 3.8	44.6 ± 2.6	48.2 ± 5.3	19.0 ± 4.9
K562	55.9 ± 4.9	21.8 ± 6.0	19.6 ± 2.3	4.2 ± 1.5
MCF-7	>100	56.3 ± 5.8	>100	28.0 ± 2.9

Note:

* Each value represents the average of five different experiments ± standard deviation.

Table 3 Evaluation of physiological parameters in mice treated with the different formulations

Samples	Elapsed time1 (days)	Mean weight loss2 (g)	50% survival3 (days)
Control	6	~3.2	24
Pure Sq-Na	6	~2.6	22
Ara-C (100 mg/kg)	14	~1.4	38
Physical mixture Ara-C/pure Sq-Na	15	~1.0	39
Sq-Ara-C (50 mg/kg)	46	~0.4	70

Note:

1 Time of appearance of symptoms of leukemia;

2 weight loss in mice not inoculated with L1210R cells;

3 days elapsed resulting in death of 50% of mice.

Figure 2 Survival profile of mice inoculated intravenously with 1 × 10⁵ L1210R cells and treated with the different formulations.

Figure 3 Biodistribution of [³H]CHE radiolabeled Sq-Ara-C nanoaggregates in DBA/2 mice as a function of time.

Figure 4 Pharmacokinetic profiles for free Ara-C and Sq-Ara-C in DBA/2 mice following intravenous administration of a 1 mg/kg dose.

Note: Data are the mean of three independent experiments ± standard deviation.

Scheme 1 Synthesis of 4-(N)-1,1′,2-tris-nor-squalenoyl-cytarabine (Sq-Ara-C, compound 3) starting from 1,1′,2-tris-nor-squalene aldehyde (compound 1), which was first oxidized into 1,1′,2-tris-nor-squalene acid (compound 2) and then conjugated with Ara-C.