Abplatin(IV) Inhibited Tumor Growth On A Patient Derived Cancer Model of Hepatocellular Carcinoma And Its Comparative Multi-Omics Study With Cisplatin

Background: Cisplatin is the most common antitumor alkylating agent of platinum(II) (Pt(II)) in clinic, however it had many side effects. It is necessary to develop low toxicity platinum(IV) (Pt(IV)) drugs. Multi-omics was frequently used to help one understand the mechanism of a certain therapy at the molecular level. Little was known about the mechanism of Pt(IV) drugs, which may be benifical for clinical translation. Methods: We developed a Pt(IV) drug of cisplatin with two hydrophobic aliphatic chains and further encapsulated it with a drug carrier human serum albumin (HSA) to prepare Abplatin(IV). Transcriptomics, metabolomics and lipidomics were performed to clarify the mechanism of Pt(IV) drugs. T-test assay and fold change were used to find the differential substances.Results: We had further shown Abplatin(IV) had better tumor-targeting performance and greater tumor inhibtion rate than cisplatin. Lipidomics study showed that Abplatin(IV) might induce the changes of BEL-7404 cell membrane, and caused the disorder of glycerophospholipids and sphingolipids. In addition, transcriptomics and metabolomics study showed that Abplatin(IV) mainly disturbed more significant purine metabolism pathway than cisplatin.Conclusions: This research highlighted the development of Abplatin(IV) and the use of multi-omics to help one understand the mechanism of action of prodrugs and their DDS, which was the key to the clinical translation of them.

Small Extracellular Vesicles from Human Amniotic Fluid Samples as Promising Theranostics

Since the first evidence that stem cells can provide pro-resolving effects via paracrine secretion of soluble factors, growing interest has been addressed to define the most ideal cell source for clinical translation. Leftover or clinical waste samples of human amniotic fluid obtained following prenatal screening, clinical intervention, or during scheduled caesarean section (C-section) delivery at term have been recently considered an appealing source of mesenchymal progenitors with peculiar regenerative capacity. Human amniotic fluid stem cells (hAFSC) have been demonstrated to support tissue recovery in several preclinical models of disease by exerting paracrine proliferative, anti-inflammatory and regenerative influence. Small extracellular vesicles (EVs) concentrated from the hAFSC secretome (the total soluble trophic factors secreted in the cell-conditioned medium, hAFSC-CM) recapitulate most of the beneficial cell effects. Independent studies in preclinical models of either adult disorders or severe diseases in newborns have suggested a regenerative role of hAFSC-EVs. EVs can be eventually concentrated from amniotic fluid (hAF) to offer useful prenatal information, as recently suggested. In this review, we focus on the most significant aspects of EVs obtained from either hAFSC and hAF and consider the current challenges for their clinical translation, including isolation, characterization and quantification methods.

Conjugation of VEGFR1/R2-targeting peptide with gold nanoparticles to enhance antiangiogenic and antitumoral activity

Background Inhibition of tumor angiogenesis through simultaneous targeting of vascular endothelial growth factor receptor (VEGFR)-1 and -2 is highly efficacious. An antagonist peptide of VEGFA/VEGFB, referred to as VGB3, can recognize and neutralize both VEGFR1 and VEGFR2 on the endothelial and tumoral cells, thereby inhibits angiogenesis and tumor growth. However, improved efficacy and extending injection intervals is required for its clinical translation. Given that gold nanoparticles (GNPs) can enhance the efficacy of biotherapeutics, we conjugated VGB3 to GNPs to enhance its efficacy and extends the intervals between treatments without adverse effects. Results GNP–VGB3 bound to VEGFR1 and VEGFR2 in human umbilical vein endothelial (HUVE) and 4T1 mammary carcinoma cells. GNP–VGB3 induced cell cycle arrest, ROS overproduction and apoptosis and inhibited proliferation and migration of endothelial and tumor cells more effectively than unconjugated VGB3 or GNP. In a murine 4T1 mammary carcinoma tumor model, GNP–VGB3 more strongly than VGB3 and GNP inhibited tumor growth and metastasis, and increased animal survival without causing weight loss. The superior antitumor effects were associated with durable targeting of VEGFR1 and VEGFR2, thereby inhibiting signaling pathways of proliferation, migration, differentiation, epithelial-to-mesenchymal transition, and survival in tumor tissues. MicroCT imaging and inductively coupled plasma mass spectrometry showed that GNP–VGB3 specifically target tumors and exhibit greater accumulation within tumors than the free GNPs. Conclusion Conjugation to GNPs not only improved the efficacy of VGB3 peptide but also extended the intervals between treatments without adverse effects. These results suggest that GNP–VGB3 is a promising candidate for clinical translation. Graphical Abstract