Tailoring polymeric micelles for improved olaparib solubility and drug release

Xia & He Publishing Inc.May 23 2024

Background and aims

Olaparib is a selective poly (ADP-ribose) polymerase inhibitor. However, its clinical application is hindered by low solubility and undesired pharmacokinetic profiles (e.g., relatively short circulation). Therefore, the present study aims to exploit polymeric micelles as a safe solubilizer and nanocarrier of olaparib, in order to improve its solubility and pharmacokinetics.

Methods

Poly (ε-caprolactone)-co-poly (benzyl 5-methyl-2-oxo-1,3-dioxane-5-carboxylate), i.e., benzyl-functionalized trimethylene carbonate)-b-poly (ethylene glycol) (P(CL-co-TMC-Bz)-PEG), was synthesized by ring-opening polymerization, and used to prepare the π-π-stacked polymeric micelles for olaparib encapsulation. A series of olaparib-loaded micelles with different polymer concentrations and wt% loadings were prepared using different methods to investigate the effect of formulation variables on the size of polymeric micelles and drug loadings. In addition, the in vitro release of olaparib from the micelles, and the cytotoxicity of micellar olaparib formulations on the SKOV3 tumor cell line were evaluated by UV spectrophotometry and CCK-8 assay, respectively. Finally, the blood circulation kinetics and side effects of the incorporated olaparib in the micelles and free olaparib were investigated in SD rats using ultra-high performance liquid chromatography analysis and H&E staining, respectively.

Results

It was found that P(CL11-co-TMC-Bz5)-PEG micelles served as a safe and excellent solubilizer for olaparib, and that the solubilization capacity was easily tailored by adjusting the polymer concentration. In addition, when loaded in micelles, olaparib exhibited a sustained release behavior in vitro, and obvious cytotoxicity on SKOV3 cells. The in vivo studies revealed that olaparib incorporated in P(CL11-co-TMC-Bz5)-PEG polymeric micelles exhibited prolonged circulation (t1/2 = 2.00 hours), when compared to free olaparib (t1/2 ≤ 0.25 hours), and excellent safety. However, in terms of taking advantage of the EPR effect of the micelle delivery system to achieve the targeted olaparib delivery, the circulation time of olaparib in the micelles remained rather short.

Conclusions

The present study revealed that polymeric micelles based on P(CL11-co-TMC-Bz5)-PEG can improve the solubility of olaparib to up to 4 mg/mL in water, and that the solubilization capacity can be further improved by adjusting the polymer concentration, as needed. Therefore, P(CL11-co-TMC-Bz5)-PEG polymeric micelles can be considered as a safe solubilizer for olaparib. In addition, olaparib-loaded micelles had a good sustained release ability of olaparib in vitro, and had obvious cytotoxicity on SKOV3 cells. Furthermore, the in vivo pharmacokinetic studies revealed the prolonged blood circulation of olaparib incorporated in the micelles, when compared to free olaparib. However, in terms of taking advantage of the EPR effect of the micelle delivery system to achieve targeted olaparib delivery, the circulation time of olaparib in the micelles remained rather short. Therefore, further optimization by e.g. chemical crosslinking and drug conjugation, is needed to improve the retention of olaparib-loaded polymeric micelles in the blood circulation, and benefit from these as carriers, in order to achieve the targeted delivery of the payload in pathological tissues.