Olaparib (OLA), the first FDA-approved PARP inhibitor, has been approved successively for monotherapy or maintenance treatment of ovarian, breast and pancreatic cancer. Unfortunately, the poor solubility and bioavailability of OLA have limited its application. In this study, novel drug-drug co-amorphous systems of OLA with five nonsteroidal anti-inflammatory drugs (NSAIDs), including flurbiprofen (FLU), ketoprofen (KET), ibuprofen (IBU), diclofenac (DIC) or indomethacin (IND), were prepared for improving the aqueous solubility of OLA and achieving combination therapy against ovarian cancer. These new co-amorphous products were confirmed by powder X-ray diffraction, differential scanning calorimetry, and Fourier transform infrared spectroscopy. Five co-amorphous systems were more soluble and released faster than the crystalline OLA in pH 6.8 buffer, and OLA-DIC and OLA-IND showed superior physicochemical stability under accelerated storage conditions. The antitumor activities of OLA-FLU, OLA-KET, OLA-IBU and OLA-DIC against OVCAR3 cell line were approximately increased by 3.5, 2.4, 2.7, and 6.0-fold than that of OLA, respectively. Moreover, pharmacokinetic studies of co-amorphous OLA-DIC in rats revealed that the OLA exhibited 6.14-fold improvement in AUC 0-t value compared with crystalline OLA. Therefore, our study suggested that OLA-NSAIDs co-amorphous systems showed the great potentials to improve the solubility, dissolution behaviors, and bio-pharmaceutical performance of OLA.
Mengdi Song,Zhenjing Liu,Zhou Fang,Jiaqi Xu,Xinran Gao,Min Zhang,Kehai Liu
Olaparib (Ola) mediated maintenance therapy is regarded as the most important way to prolong the survival period of pancreatic cancer patients after chemotherapy. However, it only has a “synthetic lethal” effect on patients with BRCA mutations. This is because in tumors non-BRCA mutations, the homologous recombination repair (HRR) function still exists. Interference with the core protein RAD51 in the BRCA pathway can lead to defects in HRR, making patients with non-BRCA mutations sensitive to Ola treatment, which is expected to broaden the adaptation range of Ola. In this study, Bacillus Clausii ( B. clausii ) was utilized to obtain the engineered extracellular vesicles (eBEVs) carrying RAD51 siRNA and expressing G3-C12 polypeptide by transforming the co-expression plasmid, which will be used for embedding Ola. Therefore, a new type of oral drug delivery system eBEVs-Ola co-carrying Ola and siRNA was successfully constructed. Its gastrointestinal protection and intestinal epithelial crossing properties enable oral administration, while the G3-C12 targeting function enable pancreatic cancer concentration. After cell entry, RAD51 siRNA specifically silenced RAD51 to block HRR, and Ola simultaneously acted on the PARP enzyme and jointly inhibited DNA damage repair, thereby sensitizing non-BRCA-mutated pancreatic cancer cells to Ola through a synthetic lethal interaction. The results showed that eBEVs-Ola exhibited good targeting and maintenance therapeutic effects in the mouse model of human pancreatic tumor xenotransplantation, and had no obvious toxicity. eBEVs-Ola, as a safe and effective oral-administered drug delivery system, may provide a potential strategy for the maintenance treatment of patients non-BRCA mutations.
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