Development and Statistical Optimization of Polymer-Based Nanoparticulate Delivery System for Enhancing Cytarabine Efficacy in Leukemia Treatment

Purpose

Cytarabine, an antimetabolite antineoplastic agent, has been used to treat acute myeloid leukemia. However, due to its short half-life, maintaining an optimal plasma concentration necessitates continuous intravenous administration, which may result in toxicity to healthy cells and tissues. The purpose of the current investigation was to design and optimize biodegradable poly (lactic acid) (PLA) nanoparticles (NPs) for improved delivery of cytarabine against acute myeloid leukemia.

Method

The NPs were prepared using a double emulsion evaporation technique. A 3² factorial design was employed to optimize the particle size and entrapment efficiency. The developed NPs were analyzed for particle size, polydispersity, and zeta potential using the dynamic light scattering (DLS) technique. The morphological analysis of NPs was conducted using transmission electron microscopy (TEM). The compatibility of drugs and excipients was examined using attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy. The entrapment efficiency of NPs was determined using an indirect method. In vitro drug release was carried out by dialysis bag method. The toxicity of NPs to leukemic cells (KG-1) was determined by MTT assay. The in vivo pharmacokinetic study was performed on rabbits.

Results

A total of nine formulations (PL1-PL9) were developed, with particle sizes ranging from 135.8 ± 1.7 to 295.0 ± 3.2 nm and entrapment efficiencies ranging from 46.27 ± 5.30 to 70.33 ± 0.80%. The optimized formulation (PL9) exhibited a reduced particle size (179.3 ± 1.9 nm), improved entrapment efficiency (56.13 ± 6.50%), spherical morphology, negative zeta potential (−17 mV), better compatibility between the polymer and drug, and conversion of cytarabine from a crystalline to an amorphous form in the formulation. The in vitro release pattern of cytarabine from NPs exhibited a first quick release (18–40%), followed by a sustained release for up to 48 h. The sustained release further enhanced the toxicity of cytarabine-loaded PLA NPs to KG-1 cell lines. The in vivo pharmacokinetics study showed a better pharmacokinetic profile of PL9 than the control.

Conclusion

The study recommends that cytarabine-containing PLA NPs are a promising approach to overcome dose-limiting toxicity. The sustained release mechanism ensures maximum anti-leukemic effect and better pharmacokinetics.

Graphical Abstract