Preclinical Therapeutic Assessment of a New Chemotherapeutics [Dichloro(4,4’-Bis(2,2,3,3-Tetrafluoropropoxy) Methyl)-2,2’-Bipryridine) Platinum] in an Orthotopic Patient-Derived Xenograft Model of Triple-Negative Breast Cancers

Abstract

Cisplatin is one of the most common therapeutics used in treatments of several types of cancers. To enhance cisplatin lipophilicity and reduce resistance and side effects, a polyfluorinated bipyridine-modified cisplatin analogue, dichloro[4,4’-bis(2,2,3,3-tetrafluoropropoxy)methyl)-2,2’-bipryridine] platinum (TFBPC), was synthesized and therapeutic assessments were performed. TFBPC displayed superior effects in inhibiting the proliferation of several cisplatin-resistant human cancer cell lines, including MDA-MB-231 breast cancers, COLO205 colon cancers and SK-OV-3 ovarian cancers. TFBPC bound to DNA and formed DNA crosslinks that resulted in DNA degradation, triggering the cell death program through the PARP/Bax/Bcl-2 apoptosis and LC3-related autophagy pathway. Moreover, TFBPC significantly inhibited tumor growth in both animal models which include a cell line-derived xenograft model (CDX) of cisplatin-resistant MDA-MB-231, and a patient-derived xenograft (PDX) model of triple-negative breast cancers (TNBCs). Furthermore, the biopsy specimen from TFBPC-treated xenografts revealed decreased expressions of P53, Ki-67 and PD-L1 coupled with higher expression of cleaved caspase 3, suggesting TFBPC treatment was effective and resulted in good prognostic indications. No significant pathological changes were observed in hematological and biochemistry tests in blood and histological examinations from the specimen of major organs. Therefore, TFBPC is a potential candidate for treatments of patients suffering from TNBCs as well as other cisplatin-resistant cancers.

Preclinical Assessment of Enhanced Chemodynamic Therapy by an FeMnOx-Based Nanocarrier: Tumor-Microenvironment-Mediated Fenton Reaction and ROS-Induced Chemotherapeutic for Boosted Antitumor Activity

“…Neither FeMnO x NPs nor FeMnO x @CPT induced any changes in biochemical parameters, including blood urea nitrogen (BUN), creatinine (CREA), aminotransferase of aspartate (ALT), and alanine aminotransferase (AST), all of which stayed within the usual physiological range. Significant changes were not observed in the amounts of red and white blood cells, and the total white counts in the FeMnO x @CPT-treated animals remained within the norm of the WBC count . Similarly, H&E staining of collected organs after mice were sacrificed on the 14th day of treatment served to evaluate the toxicity of FeMnO x NPs and FeMnO x @CPT.…”

“…The methodology utilized for xenograft models of breast cancer was adapted from previously published studies. , In this work, female SCID mice aged 5 weeks were acquired from BioLasco Company (Taipei, Taiwan) and raised at the animal facility of Taipei Medical University with ad libitum feeding and a 12 h light–dark cycle. Following a week of acclimation, each mouse received an implant of 2 × 10 6 MDA-MB-231 cells.…”

“…Significant changes were not observed in the amounts of red and white blood cells, and the total white counts in the FeMnO x @CPT-treated animals remained within the norm of the WBC count. 34 Similarly, H&E staining of collected organs after mice were sacrificed on the 14th day of treatment served to evaluate the toxicity of FeMnO x NPs and FeMnO x @CPT. Correspondingly, the results of H&E staining (Figure 9h) showed no apparent damage to the major organs compared to nontreated mice, suggesting the good biocompatibility of FeMnO x and FeMnO x @CPT.…”

Engineering H2O2 Self-Supplying Platform for Xdynamic Therapies via Ru–Cu Peroxide Nanocarrier: Tumor Microenvironment-Mediated Synergistic Therapy

“…The approach employed for xenograft models of breast cancer was derived from previously published studies. − The study utilized female SCID mice, aged 5 weeks, obtained from BioLasco Company in Taipei, Taiwan. The mice were then housed at the animal facility of Taipei Medical University, where they were provided with unrestricted access to food and subjected to a 12-h light-dark cycle.…”