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Nanocrystallization Improves the Solubilization and Cytotoxic Effect of a Poly (ADP-Ribose)-Polymerase-I Inhibitor
Amer S Alali1, Mohd Abul Kalam2,3, Mohammed Muqtader Ahmed1
1Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj 11942, Saudi Arabia.
Abstract:
Olaparib (OLA) is an anticancer agent that acts by inhibiting the poly (ADP-ribose)-polymerase-I (PARP-I). Due to its low solubility and low permeability, it has been placed as a BCS Class-IV drug and hence its clinical use is limited. In this study, we develop the nanocrystals of OLA as a way to improve its solubility and other performances. The OLA-NCs were prepared by antisolvent precipitation method through homogenization and probe sonication technique using a novel amphiphilic polymeric stabilizer (Soluplus®). Particle characterization resulted approximately 103.13 nm, polydispersity-index was 0.104 with positive zeta-potential of +8.67 mV. The crystal morphology by SEM of OLA-NCs (with and without mannitol) exhibited nano-crystalline prism-like structures as compared to the elongated OLA-pure. The DSC, XRD and FTIR were performed to check the interaction of Soluplus, mannitol and OLA did not exhibit any physical interaction among the OLA, Soluplus® and mannitol that is indicated by the presence of parent wave number peak. Two-fold increased solubility of OLA was found in PBS with Soluplus® from the NCs (69.3 ± 6.2 µgmL−1) as compared to pure drug (35.6 ± 7.2 µgmL−1). In vitro release of drug from OLA-NCs was higher (78.2%) at 12 h at pH 6.8 and relatively lower (53.1%) at pH 1.2. In vitro cellular cytotoxicity and anticancer effects were examined on MCF-7 cells. OLA-NCs were found effectively potent to MCF-7 cells compared with OLA-pure with approximately less than half IC50 value during MTT assay. Estimation of p53, Caspase-3 and Caspase-9 in MCF-7 cells indicated that OLA-NCs have significantly (p < 0.05) increased their expressions. After single oral dose in rats, 12 h plasma drug concentration-time profile indicated approximately 2.06-, 2.29-, 2−25- and 2.62-folds increased Cmax, AUC0-12 h, AUC0-∞ and AUMC0-∞, respectively, from the NCs as compared to OLA-pure. Storage stability indicated that the OLA-NCs was physically and chemically stable at 4 °C, 25 °C and 40 °C up to 6-months. Overall, OLA-NCs were deliberated; its potential feasibility to overwhelm the formulation challenges related to poorly soluble drugs and its future clinical applications.
Insights
This study developed nanocrystals of the anticancer drug Olaparib (OLA) to overcome its poor solubility and limited clinical use. The resulting Olaparib nanocrystals (OLA-NCs) showed enhanced solubility, improved anticancer efficacy in cell studies, and significantly increased bioavailability in rats.
Area of Science:
- Pharmaceutical Sciences
- Nanotechnology
- Drug Delivery
Background:
- Olaparib (OLA), a PARP-I inhibitor, is an effective anticancer agent but faces limited clinical application due to its poor solubility and permeability (BCS Class-IV drug).
- Developing advanced drug delivery systems is crucial to enhance the therapeutic performance of poorly soluble drugs like Olaparib.
Purpose of the Study:
- To formulate and characterize Olaparib nanocrystals (OLA-NCs) using Soluplus® as a stabilizer to improve Olaparib's solubility, dissolution, and anticancer efficacy.
- To evaluate the in vitro and in vivo performance of OLA-NCs compared to pure Olaparib.
Main Methods:
- Olaparib nanocrystals (OLA-NCs) were prepared via antisolvent precipitation using homogenization and probe sonication with Soluplus®.
- Particle size, zeta potential, morphology (SEM), drug-excipient interactions (DSC, XRD, FTIR), solubility, in vitro release, and cellular cytotoxicity (MCF-7 cells) were assessed.
- In vivo pharmacokinetic studies in rats and storage stability tests were conducted.
Main Results:
- OLA-NCs exhibited a particle size of ~103 nm with a positive zeta potential (+8.67 mV), indicating good stability.
- Solubility of OLA-NCs in PBS was doubled compared to pure OLA, and in vitro release was significantly higher at pH 6.8.
- OLA-NCs demonstrated enhanced in vitro anticancer activity against MCF-7 cells (lower IC50) and significantly increased expression of p53, Caspase-3, and Caspase-9.
- In vivo studies in rats showed a 2- to 2.6-fold increase in key pharmacokinetic parameters (Cmax, AUC) for OLA-NCs compared to OLA-pure.
- The OLA-NC formulation remained physically and chemically stable for up to 6 months under various storage conditions.
Conclusions:
- The developed Olaparib nanocrystals (OLA-NCs) effectively enhance the solubility, dissolution, and oral bioavailability of Olaparib.
- OLA-NCs show improved in vitro anticancer potency and are a promising formulation strategy to overcome the challenges associated with poorly soluble drugs for potential clinical applications.
