Carbonic anhydrase (CA) IX overexpresses exclusively on cell membranes of hypoxic tumors, regulating the acidic tumor microenvironment. Small molecules of CA inhibitor modified with short peptide successfully achieve CA IX–targeted self-assembly that localizes CA inhibitors on hypoxic cancer cell surfaces and enhances their inhibition efficacy and selectivity. CA IX–related endocytosis also promotes selective intracellular uptake of these nanofibers under hypoxia, in which nanofiber structures increase in size with decreasing pH. This effect subsequently causes intracellular acid vesicle damage and blocks protective autophagy. The versatility of tunable nanostructures responding to cell milieu impressively provokes selective toxicities and provides strategic therapy for hypoxic tumors. Moreover, in vivo tests demonstrate considerable antimetastatic and antiangiogenesis effects in breast tumors, and particularly remarkable enhancement of antitumor efficacy in doxorubicin administration. With its biocompatible components and distinctive hypoxia therapies, this nanomaterial advances current chemotherapy, providing a new direction for hypoxic cancer therapy.
Four new cadmium(II) coordination polymers (CPs), {[Cd(Hpptpd)(H2bptta)]·8H2O} n (1), {[Cd2(Hpptpd)2(bptta)(H2O)2]·4H2O} n (2), {[Cd2(pptpz)(bpta)(H2O)]·H2O} n (3), and {[Cd(Hpptpz)(bpba)]·2H2O} n (4) (Hpptpd = 2-(3-(4-(pyridin-4-yl)phenyl)-1H-1,2,4-triazol-5-yl)pyridine, Hpptpz = 2-(3-(4-(pyridin-4-yl)phenyl)-1H-1,2,4-triazol-5-yl)pyrazine, H4bptta = 3,3′,5,5′-biphenyltetracarboxylic acid, H3bpta = 3,4′,5-biphenyltricarboxylic acid, H2bpba = 3,4′-biphenylbicarboxylic acid), were synthesized under hydrothermal conditions. The CPs were structurally characterized by single-crystal X-ray diffraction analyses and further characterized by infrared spectra (IR), elemental analyses, powder X-ray diffraction (PXRD), and thermogravimetric analyses (TGA). Complex 1 exhibits an unusual 2D + 2D → 2D parallel interpenetrated 63-hcb network. The adjacent 2D networks are interdigitated with each other to form the resulting three-dimensional (3D) supramolecular architecture through the interbilayer π···π stacking between Hpptpd ligands and nonclassical C–H···O hydrogen bonds. Complex 2 is a one-dimensional (1D) molecular ladder along the a direction and further extended via hydrogen bonds into the 3D supramolecular framework. Complex 3 exhibits a novel complicated 3D (3,4,4,5)-connected framework with the Schläfli symbol of (4·65)(4·67·82)(63)(64·82). Complex 4 manifests an intriguing layered structure with 5-connected cadmium atom as a unique node and can be simplified to an Archimedean (33·44·53) cem topology with triangular and rectangular circuits. The topology of 4 could be alternately simplified to a 3,4-connected binodal layer with a V2O5-type network. The thermal stabilities and photoluminescence behaviors of them were also discussed.
The development of an intelligent biomaterial system that can efficiently accumulate at the tumor site and release a drug in a controlled way is very important for cancer chemotherapy. PEG is widely selected as a hydrophilic shell to acquire prolonged circulation time and enhanced accumulation at the tumor site, but it also restrains the cellular transport and uptake and leads to insufficient therapeutic efficacy. In this work, a PEG-detachable pH-responsive polymer that forms micelles from copolymer cholesterol grafted poly(ethylene glycol) methyl ether-Dlabile -poly(β-amino ester)-Dlabile -poly(ethylene glycol) methyl ether (MPEG-Dlabile -PAE-g-Chol) is developed to overcome the aforementioned challenges based on pH value changes among normal physiological, extracellular (pHe), and intracellular (pHi) environments. PEGylated doxorubicin (DOX)-loaded polymeric micelles (DOX-PMs) can accumulate at the tumor site via an enhanced permeability and retention effect, and the PEG shell is detachable induced by cleavage of the pHe-labile linker between the PEG segment and the main chain. Meanwhile, the pHi-sensitive poly(β-amino ester) segment is protonated and has a high positive charge. The detachment of PEG and protonation of PAE facilitate cellular uptake of DOX-PMs by negatively charged tumor cells, along with the escape from endo-/lysosome due to the “proton-sponge” effect. The DOX molecules are controlled release from the carriers at specific pH values. The results demonstrate that DOX-PMs have the capability of showing high therapeutic efficacy and negligible cytotoxicity compared with free DOX in vitro and in vivo. Overall, we anticipate that this PEG-detachable and tumor-acidity-responsive polymeric micelle can mediate effective and biocompatible drug delivery “on demand” with clinical application potential.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.