Breast cancer (BC) is one of the most common malignancies in women and often accompanied by inflammatory processes.Cyclooxygenase-2 (COX-2) playsavital role in the progression of BC,c orrelating with the expression of programmed death-ligand 1(PD-L1). Overexpression of PD-L1 contributes to the immune escape of cancer cells,a nd its blockade would stimulate anticancer immunity.T wo multispecific platinum(IV) complexes DNP and NP were prepared using non-steroidal antiinflammatory drug naproxen (NPX) as axial ligand(s) to inhibit the BC cells.D NP exhibited high cytotoxicity and antiinflammatory properties superior over NP, cisplatin and NPX;m oreover,i td isplayed potent antitumor activity and almost no general toxicity in mice bearing triplenegative breast cancer (TNBC). Mechanistic studies revealed that DNP could downregulate the expression of COX-2 and PD-L1 in vitro and vivo,inhibit the secretion of prostaglandin, reduce the expression of BC-associated protein BRD4 and phosphorylation of extracellular signal-regulated kinases 1/2 (Erk1/2), and block the oncogene c-Myc in BC cells.T hese findings demonstrate that DNP is capable of intervening in inflammatory,i mmune,a nd metastatic processes of BC,t hus presenting anew mechanism of action for anticancer platinum-(IV) complexes.T he multispecificity offers as pecial superiority for DNP to treat TNBC by combining chemotherapyand immunotherapyi none molecule.
Platinum(iv) prodrugs targeting the DNA repair mechanism downregulate myeloid cell leukemia-1 (Mcl-1) and homologous recombination proteins (RAD51, BRCA2), thereby enhancing cytotoxicity against cisplatin-resistant cancer cells.
Temporal control of delivery and release of drugs in tumors are important in improving therapeutic outcomes to patients. Here, we report a sequential stimuli-triggered in situ self-assembly and disassembly strategy to direct delivery and release of theranostic drugs in vivo. Using cisplatin as a model anticancer drug, we design a stimuli-responsive small-molecule cisplatin prodrug (P-CyPt), which undergoes extracellular alkaline phosphatase-triggered in situ self-assembly and succeeding intracellular glutathione-triggered disassembly process, allowing to enhance accumulation and elicit burst release of cisplatin in tumor cells. Compared with cisplatin, P-CyPt greatly improves antitumor efficacy while mitigates off-target toxicity in mice with subcutaneous HeLa tumors and orthotopic HepG2 liver tumors after systemic administration. Moreover, P-CyPt also produces activated near-infrared fluorescence (at 710 nm) and dual photoacoustic imaging signals (at 700 and 750 nm), permitting high sensitivity and spatial-resolution delineation of tumor foci and real-time monitoring of drug delivery and release in vivo. This strategy leverages the advantages offered by in situ self-assembly with those of intracellular disassembly, which may act as a general platform for the design of prodrugs capable of improving drug delivery for cancer theranostics.
Cancer
is characterized by abnormal cellular energy metabolism, which preferentially
switches to aerobic glycolysis rather than oxidative phosphorylation
as a means of glucose metabolism. Many key enzymes involved in the
abnormal glycolysis are potential targets of anticancer drugs. Platinum(IV)
complexes are potential anticancer prodrugs and kinetically more inert
than the platinum(II) counterparts, which offer an opportunity to
be modified by functional ligands for activation or targeted delivery.
A novel platinum(IV) complex, c,c,t-[Pt(NH3)2Cl2(C10H15N2O3S)(C2HO2Cl2)] (DPB), was designed to explore the
effects of axial ligands on the reactivity and bioactivity of the
complex as well as on tumor energy metabolism. The complex was characterized
by electrospray ionization mass spectrometry and multinuclear (1H, 13C, and 195Pt) NMR spectroscopy.
The introduction of dichloroacetate (DCA) markedly increases the lipophilicity,
reactivity, and cytotoxicity of the complex and blocks the growth
of cancer cells having active glycolysis, and the introduction of
biotin (C10H16N2O3S) enhances
the tumor-targeting potential of the complex. The cytotoxicity of
DPB is increased dramatically in a variety of cancer cell lines as
compared with the platinum(IV) complex PB without the DCA group. DPB
alters the mitochondrial membrane potential and disrupts the mitochondrial
morphology. The levels of mitochondrial and cellular reactive oxygen
species are also decreased. Furthermore, the mitochondrial function
of tumor cells was impaired by DPB, leading to the inhibition of both
glycolysis and glucose oxidation and finally to the death of cancer
cells via a mitochondria-mediated apoptotic pathway. These findings
demonstrate that DPB suppresses cancer cells mainly through altering
metabolic pathways and highlight the importance of dual-targeting
for the efficacy of anticancer drugs.
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