Search

To track an intact biological process inside cells, continuous showing of the assembly/disassembly process is needed and fluorescence is advantageous in characterizing these processes. However, using fluorescence "on/off" to observe a sequential assembly/disassembly process in living cells has not been reported. Herein, we rationally designed a probe PEA-NBD-Yp and employed its fluorescence "on/off" to trace tandem assembly/disassembly of nanofibers in living HeLa cells. In vitro experiments validated that PEA-NBD-Yp could be efficiently dephosphorylated by ALP to yield PEA-NBD-Y , which self-assembled into nanofibers with the NBD fluorescence "on". Also, the PEA-NBD-Y nanofiber was disassembled by GSH, accompanied by fluorescence "off". Living cell imaging (together with ALP-inhibition or GSH-blocking) experiments sequentially showed the self-assembling nanofibers on the cell outer membrane with fluorescence "on" (On 1 ), translocated inside cells (On 2 ), and disassembled by GSH with fluorescence "off" (Off 2 ). We anticipate that our strategy of one probe conferring temporal "on/off" fluorescence signals might provide people with a new tool to deeply understand a biological event in living cells in the near future.

Paclitaxel (Ptx), a type of microtubule depolymerization inhibitor, is one of the main components in gastric cancer chemotherapy. Some studies have demonstrated that tetrandrine (Tet), a bisbenzylisoquinoline alkaloid, has potential antitumor effects in several cancers. Aside from the direct anticancer effect, Tet is proved to synergistically enhance the antitumor effect of Ptx in gastric cancer. However, the application of the combinational strategy is limited by the poor solubility of both drugs. Nanodrug delivery systems including polymeric nanoparticles, self-assembled nanofibers, hydrogels, etc., hold the potential to meet the need. Here, a novel supramolecular nanomaterial, based on the concept of "carrier-free nanodrugs", is reported as a feasible platform for synergistic drug delivery. Ptx-SA-RGD is obtained through the conjugation of Ptx and the tumor-specific peptide RGD (arginine-glycine-aspartic acid) with succinic acid (SA) as a linker. Ptx-SA-RGD could self-assemble into Ptx nanofibers (P-NFs) with high drug-loading efficiency. Tet was then encapsulated into P-NFs to acquire novel Ptx and Tet coloaded self-assembled nanofibers (P/T-NFs). The uptake study shows the dynamic internalization of P/T-NFs by the gastric cancer cell line MGC-803. P/T-NFs significantly triggered the accumulation of reactive oxygen species (ROS) in gastric cancer cells MGC803 and further decreased the mitochondrial membrane potential, which led to the induction of mitochondrial apoptosis with superior cytotoxicity against free drugs. Moreover, P/T-NFs suppressed the expressions of p-STAT3 and p-JAK, initiated cytochrome- C release, and promoted caspase protein expression. Furthermore, P/T-NFs demonstrated the strongest tumor-delaying effect as well as the lowest toxicity. Therefore, self-assembled nanofibers of P/T-NFs demonstrated an increase of the mitochondrial apoptosis level and a stronger antitumor effect both in vitro and in vivo, which could be a potential way to enhance the clinical efficacy and reduce the side-effects of Ptx in gastric cancer.

The development of molecules with immune stimulatory properties is crucial for cancer immunotherapy. In this work, we combined two peptide-based molecules, tuftsin (TKPR) and Nap-GDFDFDY, to develop a novel self-assembling molecule Nap-GDFDFDYTKPR (Comp.3), which has strong CD8+ T cell stimulatory properties. Comp.3 could self-assemble into nanofibers and hydrogels, which significantly improved the stability of tuftsin against enzyme digestion. The nanofibers of Comp.3 enhanced the phagocytic activity of macrophages, promoted the maturation of DCs, and stimulated the expression of cytokines. In addition, it demonstrated an excellent anti-tumor efficacy in vivo by eliciting a strong CD8+ T immune response. Taken together, our observations revealed a powerful immune stimulating nanomaterial that is a promising compound for cancer immunotherapy.

Recent studies focused on the nanodelivery system of paclitaxel (Ptx) to overcome the poor solubility and hypersensitivity of Ptx caused by the application of Cremophor EL as a solvent. Although many studies use different types of polymers as carriers to prepare Ptx-loaded polymeric nanoparticles, the relatively low loading efficiency of Ptx-loaded polymeric nanoparticles significantly limits its application. Here, we design and synthesize a simple conjugation of Ptx and succinic acid (Ptx-SA), which can self-assemble into nanofibers and become "carrier-free" with Ptx as the drug carrier. The highest loading efficiency of Ptx is 89.5% with a controlled release pattern. The cellular uptake study indicates the internalization of Ptx-SA nanofibers by A549 cells. The in vitro cytotoxicity test results indicate that Ptx-SA nanofibers were much more effective in inhibiting the proliferation of A549 cells than free Ptx, particularly at the lower working concentration. The clonogenic assay shows the enhanced effect of Ptx-SA in ameliorating the clonogenic abilities of A549 cells compared with the equivalent dose of free Ptx. Moreover, Ptx-SA significantly attenuates the expression of p-Akt and increases the expression of cleaved PARP and Caspase-3 compared to the equivalent dose of free Ptx, which demonstrates the enhanced apoptosis-inducing effect of Ptx-SA. The animal study demonstrates the superior antitumor effect of Ptx-SA compared to free Ptx. Therefore, the conjugation of Ptx with SA enables the self-assembly of Ptx-loaded nanofibers with stronger in vitro and in vivo antitumor effects, which is a promising method to improve the therapeutic efficacy of Ptx in treating lung cancer., (Copyright © 2017. Published by Elsevier B.V.)

Abstract: Development of highly efficient radiosensitizers is urgently desirable for addressing the resistance of cancer cells to ionizing radiation, which is the main reason for the failure of radiotherapy. Here, it is reported for the first time that supramolecular nanomaterials can serve as an excellent nanoplatform for developing superior radiosensitizers. A new curcumin‐based supramolecular nanofiber (Cur‐SNF) by virtue of a self‐assembling short peptide is developed, which greatly boosts the radiosensitivity of colorectal cancers to ionizing radiation. The drug–peptide conjugate Curcumin‐FFE‐CS‐EE is synthesized and can self‐assemble into small‐molecule hydrogel containing Cur‐SNFs triggered by reductant. In vitro and in vivo radiosensitization studies reveal that as compared to free curcumin Cur‐SNFs show much better performance as a radiosensitizer to sensitize colorectal cancer cells to ionizing radiation thanks to the supramolecular nanostructure. Due to the exceptionally high radiosensitization efficacy, Cur‐SNFs in combination with radiation realize significant reduction in tumor volume in vivo. Besides, the molecular mechanism studies demonstrate that Cur‐SNFs promote the radiosensitivity of colorectal cancer cells through inhibiting radiation‐induced nuclear factor kappa B activation. Cur‐SNF achieves an ultralarge sensitizer enhancement ratio at 10% cell survival value of 2.01, the highest among currently reported curcumin‐based radiosensitizers. [ABSTRACT FROM AUTHOR]