European Journal of Pharmaceutical Sciences

Bioequivalence of a hybrid pegylated liposomal doxorubicin hydrochloride injection and Caelyx®: A single-dose, randomized, multicenter, open-label, two-period crossover study in patients with advanced ovarian cancer

To evaluate the bioequivalence of a hybrid pegylated liposomal doxorubicin (PLD) hydrochloride injection with reference product Caelyx®. This multicenter, open-label, balanced, randomized, two-treatment, two-period, two-sequence, single-dose, crossover, bioequivalence study was conducted in female patients aged ≥18 years and ≤75 years with ovarian cancer, whose disease progressed or recurred after platinum-based chemotherapy, and who were scheduled to start PLD therapy. Patients were intravenously infused drugs over 1 h at 50 mg/m Both the test and reference formulations were well-tolerated and safe. The pharmacokinetic analysis for both encapsulated and unencapsulated doxorubicin was conducted in 50 patients and PK parameters were found to be comparable between test and reference products. The geometric mean ratios (90% confidence interval) of hybrid PLD/Caelyx® were; maximum measured plasma concentration (C The PLD formulation was found to be bioequivalent to Caelyx®.

Estrone-targeted PEGylated Liposomal Nanoparticles for Cisplatin (DDP) Delivery in Cervical Cancer

Cisplatin (DDP), a first-line chemo-drug for cervical cancer therapy, has limited the clinical use due to its high-dose administration and strong side effects. In this study, estrone-targeted PEGylated Liposomal DDP (ES-SSL-DDP) was prepared by thin-film hydration method and characterized. ES-SSL-DDP presented a spherical structure, with a particle size of about 97.3 nm, a surface charge of -19 mV and a high encapsulation efficiency of 47.7%. ES-SSL-DDP showed higher stability with a lower leakage rate less than 10% at 4°C. In vitro cellular uptake and internalization mechanisms in HeLa cells showed that ES-SSL-DDP had a stronger cellular uptake which was mainly via caveolin-mediated endocytosis. In vivo targeting evaluation demonstrated ES-SSL-DDP could specifically accumulated into the tumor site of HeLa-bearing mice. Cytotoxicity test on HeLa cells demonstrated the stronger cytotoxic activity of ES-SSL-DDP by MTT assay. In vivo anti-tumor efficacy of ES-SSL-DDP in HeLa tumor-bearing mice exhibited the most effective tumor inhibition. Pharmacokinetics and biodistribution of ES-SSL-DDP presented an improved metabolic behavior of the DDP. The acute toxicity demonstrated that ES-SSL-DDP could increase the LD

3D printed intrauterine device development containing dual anticancer drugs for the treatment of uterine cancer

Uterine cancer is a major global health problem and treatment frequently includes invasive surgery that severely compromises fertility. Current systemic chemotherapeutic drugs, such as paclitaxel (PCX) and carboplatin (CBP), lack an established standard protocol and their efficacy is limited. This study focuses on the development of a personalized, local drug delivery system for the treatment of uterine cancer. The intrauterine devices (IUDs) were prepared using polycaprolactone (PCL) filaments containing PCX and CBP complexed to cyclodextrin (CD) to enhance the stability and solubility of the drugs during the printing process. The fused filament fabrication (FFF) type 3D printing technique, owing to its precise computer-aided layer deposition, successfully provided a platform for geometric and dosage personalization, achieving high dimensional accuracy. Physicochemical characterization studies showed that CD inclusion complexes maintained drug stability during the printing process, confirmed by the absence of free crystalline drug. Furthermore, drug:CD complexes significantly enhanced the mechanical properties of PCL, thereby increasing strength and toughness, which are critical for intrauterine stability. In vitro release studies demonstrated a sustained, controlled release profile, exceeding 80% over 9 months for PCX and 4 months for CBP. Cytotoxicity studies showed that drug-free IUDs were non-cytotoxic and non-genotoxic to healthy L929 mouse fibroblast cells. Furthermore, in vivo studies demonstrated that IUDs did not cause dermal irritation. The drug-containing IUDs were found to be at least as effective as the drug solution on HEC-1B endometrial cancer cells. Lastly, ex vivo studies confirmed favorable bioadhesion of IUDs and high drug retention within uterine tissue. All these findings validate the FFF-type 3D printing as a promising and flexible approach for preparing personalized, biocompatible, and effective local drug delivery systems for the treatment of uterine cancer.

Gold(III) complexes with thiosemicarbazonate ligands as potential anticancer agents: Cytotoxicity and interactions with biomolecular targets

Gold(III) complexes have been studied for the past years due to their anticancer properties and great affinity to biotargets, such as enzymes and proteins, which support their pharmacological applications. Within this scope, in this work the antiproliferative activities of two Au(III)-thiosemicarbazonate complexes, [AuClL

89Zr/177Lu-labeled claudin-6 antibody exhibits effective targeted radiodiagnostic and therapeutic efficacy in gynecological cancers

Claudin 6 (CLDN6) is highly expressed in ovarian cancer (OV) and uterine corpus endometrial cancer (UCEC) but silenced in normal tissues, holding promise as an attractive target for radioimmunotherapy (RIT). This study aimed to develop zirconium-89 (⁸⁹Zr)/lutetium-177 (¹⁷⁷Lu)-labeled CLDN6 antibody (IMAB027) for immuno-positron emission tomography (immuno-PET) and RIT for OV and UCEC subcutaneous tumor models. IMAB027 was conjugated with p-SCN-Bn-DFO and DOTA-maleimide, followed by radiolabeling with

Trifluoromethyl quinoline derivative targets inhibiting HDAC1 for promoting the acetylation of histone in cervical cancer cells

Cervical cancer is the leading cause of death among gynecological malignant tumors, especially due to the poor prognosis of patients with advanced tumors due to recurrence, metastasis, and chemotherapy resistance. Therefore, exploring new antineoplastic drugs with high efficacy and low toxicity may bring new expectations in patients with cervical cancer. Natural products and their derivatives exert an antitumor activity. Therefore, in this work, combined with network pharmacology analysis and experimental validation, we investigated the anti-cervical cancer activity and molecular mechanism of a new trifluoromethyl quinoline (FKL) derivative in vivo and in vitro. FKL117 inhibited the proliferation of cervical cancer cells in a dose and time-dependent manner, induced apoptosis in HeLa cells, arrested the cell cycle in the G2/M phase, and regulated the expression of the apoptotic and cell cycle-related proteins Bcl-2, Bax, cyclin B1, and CDC2. We used online databases to obtain HDAC1 as one of the possible targets of FKL117 and the target binding and binding affinity were modeled by molecular docking. The results showed that FKL117 formed a hydrogen bond with HDAC1 and had good binding ability. We found that FKL117 targeted to inhibit the expression and function of HDAC1 and increased the acetylation of histone H3 and H4, which was also confirmed in vivo. The migration of HMGB1 from the nucleus to the cytoplasm further verified the above results. In conclusion, our study suggested that FKL117 might be used as a novel candidate for targeting the inhibition of HDAC1 against cervical cancer.

Significant growth inhibition by a bispecific affibody targeting oncoprotein E7 in both HPV16 and 18 positive cervical cancer in vitro and in vivo

The infection with HPV 16 and 18 high-risk types account for more than 80 % of cervical cancer incidence, but there is still no targeted agent against HPV for cervical cancer therapy. Our previous study constructed a bispecific affibody Z