Triple negative breast cancer (TNBC) is one of the most biologically aggressive breast cancers and lacks effective treatment options, resulting in a poor prognosis. Therefore, studies aiming to ...explore new therapeutic strategies for advanced TNBC are urgently needed. According to recent studies, microRNA-124 (miR124) not only inhibits tumour growth but also increases the sensitivity of TNBC to paclitaxel (PTX), suggesting that a platform combining PTX and miR124 may be an advanced solution for TNBC.
Herein, we constructed a stepped cleavable calcium phosphate composite lipid nanosystem (CaP/LNS) to codeliver PTX and miR124 (PTX/miR124-NP). PTX/miR124-NP exhibited superior tumor microenvironment responsive ability, in which the surface PEG layer was shed in the mildly acidic environment of tumor tissues and exposed oligomeric hyaluronic acid (o-HA) facilitated the cellular uptake of CaP/LNS by targeting the CD44 receptor on the surface of tumor cells. Inside tumour cells, o-HA detached from CaP/LNS due to the reduction of disulfide bonds by glutathione (GSH) and inhibited tumour metastasis. Then, PTX and miR124 were sequentially released from CaP/LNS and exerted synergistic antitumour effects by reversing the Epithelial-Mesenchymal Transition (EMT) process in MDA-MB-231 cells. Moreover, PTX/miR124-NP showed significant antitumour efficiency and excellent safety in mice bearing MDA-MB-231 tumours.
Based on these results, the codelivery of PTX and miR124 by the CaP/LNS nanosystem might be a promising therapeutic strategy for TNBC.
Development of high-stability and efficient nonviral vectors with low cytoxicity is important for targeted tumor gene therapy. In this study, cationic polymeric liposomes (CPLs), with similar lipid ...bilayer structure and high thermal stability, were prepared from polymeric surfactants of quaternized (carboxymethyl)chitosan with different carbon chains (dodecyl, tetradecyl, hexadecyl, and octadecyl). By comparing different factors that influence gene delivery, tetradecyl-quaternized (carboxymethy)chitosan (TQCMC) CPLs, with suitable size (184.4 ± 17.1 nm), ζ potentials (27.5 ± 4.9 mV), and productivity for synthesis TQCMC (weight yield 13.1%), were selected for gene transfection evaluation in various cancer cell lines. Although TQCMC CPLs have lower gene transfection efficiency compared with cationic liposomes (Lipofectamine 2000) in vitro, they displayed higher reporter gene delivery ability for cancer tissues (bearing U87 and SMMC-7721 tumors) in vivo after intravenous injection. TQCMC CPLs also have lower cell cytotoxicity and lower cytokine production or liver injury for BALB/c mice. We conclude that the CPLs are promising gene delivery systems that may be used to target various cancers.
Purpose
The aim of this study is to develop novel polylactide/poly(ethylene glycol) (PLA/PEG) micelles as carrier of hydrophobic drug (paclitaxel) by direct dissolution method without using any ...organic solvents. The
in vitro
and
in vivo
release properties were studied in comparison with micelles prepared by dialysis.
Methods
Drug encapsulation efficiency (EE) and loading content (LC) of the micelles were evaluated by high-performance liquid chromatography. Micelle diameters and structures were determined by dynamic light scattering and transmission electron microscopy.
In vitro
release was performed in phosphate-buffered saline (pH 7.4) at 37°C, and
in vivo
experiments were realized in lung cancer-bearing mice.
Results
Similar EE and LC values were obtained for micelles by direct dissolution method and those by dialysis. L- and D-PLA/PEG mixed micelles present higher drug encapsulation ability than separate micelles due to stereocomplexation. Micelle diameters are enlarged by drug-loading. Faster drug release was obtained for micelles by direct dissolution than those by dialysis. Compared with current clinical formulation and micelles by dialysis, paclitaxel-loaded micelles by direct dissolution showed the highest antitumor ability.
Conclusion
The L- and D-PLA/PEG mixed micelles by direct dissolution method present many advantages such as easy formulation and absence of toxic organic solvents, which shows great potential as carrier of hydrophobic drugs.
Advanced liver cancer is the most fatal malignant cancer, and the clinical outcomes of treatment are not very satisfactory due to the complexity and heterogeneity of the tumor. Combination therapy ...can efficiently enhance tumor treatment by stimulating multiple pathways and regulating the tumor immune microenvironment. Nanodrug delivery systems have become attractive candidates for combined strategies for liver cancer treatment. This study reports a nano ultrasound contrast agent (arsenic trioxide (ATO)/PFH NPs@Au‐cRGD) to integrate diagnosis and treatment for efficient ultrasound imaging and liver cancer therapy. This nanodrug delivery system promotes tumor‐associated antigens release through ATO‐induced ferroptosis and photothermal‐induced immunogenic cell death, enhancing the synergistic effects of ATO and photothermal therapy in human Huh7 and mouse Hepa1–6 cells. This drug delivery system successfully activates the antitumor immune response and promotes macrophage M1 polarization in tumor microenvironment with low side effects in subcutaneous and orthotopic liver cancer. Furthermore, tumor metastasis is inhibited and long‐term immunological memory is also established in orthotopic liver cancer when the nanodrug delivery system is combined with anti‐programmed death‐ligand 1 (PD‐L1) immunotherapy. This safe nanodrug delivery system can enhance antitumor therapy, inhibit lung metastasis, and achieve visual assessment of therapeutic efficacy, providing substantial potential in clinic applications for liver cancer.
Mechanistically, ATO‐induced ferroptosis and photothermal‐induced immunogenic cell death enhance synergistic anti‐tumor effects and immune response in liver cancer. Liver tumor metastasis is inhibited and anti‐tumor immunity is stimulated when combined with anti‐programmed cell death‐ligand 1 (PD‐L1) immunotherapy. This work provides experimental evidence for using a nano ultrasound contrast agent to combine immunotherapy and chemo‐photothermal therapy against liver cancer.
The enclosed glass capillary was chosen as the flow channel to reduce the encapsulation steps of the facile fabrication of nanostructured devices. All experiments were accomplished in microchannels, ...including 3D nanostructure synthesis, surface modification and capture/release of CTCs.
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•A new 3D nanostructured nanoforest array was constructed in glass capillaries.•The introduction of nanobranches improved CTC capture and reduced nonspecific cell capture.•Fabrication, modification and capture processes were all accomplished in capillaries.•Highly efficient capture and controllable release of CTCs were achieved.
The efficient capture of rare circulating tumor cells (CTCs) with high viability is of great importance in cancer diagnosis. The integration of three-dimensional (3D) nanobiointerfaces with capillary flow channel platforms can efficiently improve CTC capture performance by providing abundant binding sites and increasing the likelihood of contact as samples flow through the microchannels. However, due to the complex preparation processes, facile synthesis of nanostructures for use as substrates in flow channels for biomedical applications is still challenging. To reduce the encapsulation steps in the fabricating of nanostructured flow channel devices, we chose the enclosed glass capillaries as flow channels and accomplished all the experiments in the microchannels, including 3D nanostructure synthesis, surface modification and capture/release of CTCs. In this work, we constructed a novel 3D Zn(OH)F/ZnO nanoforest array in capillaries for CTC isolation via a facile microfluidic wet chemistry method. Because of the abundant binding sites of the 3D Zn(OH)F/ZnO nanoforest array, the capture efficiency was remarkably enhanced compared with that of vertical nanowires (90.3% vs 69.1%). In addition, a high release efficiency and cell viability of released cells were achieved by grafting poly(N-isopropylacrylamide) (PNIPPAm). These results may provide evidence for a novel method to fabricate hierarchical 3D substrates with a combination of biomolecule recognition and topographical interaction for biomedical applications.
CD3‐T‐cell‐engager (TCE) therapies, such as bispecific T‐cell engagers (BiTEs), have achieved extraordinary success in treating hematological malignancies and have shown therapeutic effects ...comparable with those of chimeric antigen receptor (CAR)‐T therapies. However, solid tumors are challenging to treat with TCE therapies due to tumor heterogeneity, limited tumor enrichment, an immunosuppressive tumor microenvironment (TME), a lack of pre‐existing tumor‐infiltrating lymphocytes (TILs), serious on‐target off‐tumor toxicity, and so forth. Thanks to the increased understanding of resistance mechanisms and novel technologies, the next generation of TCE therapies for solid tumors is emerging. We focus on summarizing the latest progress in CD3‐based TCE therapies and discussing the future perspective of TCE therapeutic strategies against solid tumors. This perspective highlighted novel multitarget TCE therapies that integrated multiple functionalities to enhance antitumor efficacy while minimizing off‐target toxicity. Furthermore, TCE therapies also could be rationally combined with other antitumor therapeutics, including oncolytic viruses, CAR‐T cells, and immune checkpoint blockade. Moreover, TCEs should not be limited to redirecting polyclone T cells to tumor cells. The development of novel TCEs to bridge T cells and other cells in the TME is also promising. This perspective motivates the development of the new TCE therapies strategy to broaden the armamentarium of CD3‐TCE therapies and overcome solid tumors.
T‐cell‐engagers (TCEs) have shown extraordinary success in treating hematological malignancies. However, TCE therapies for solid tumors are limited by immunosuppressive tumor microenvironment (TME), intratumor heterogeneity, and on‐target off‐tumor toxicity. The next generation of TCE‐based strategies, including intracellular neoantigen target TCEs, multitarget TCEs, combination TCEs, TCE‐armed oncolytic viruses (OVs), and TCE‐secreting chimeric antigen receptor (CAR)‐T cells, is emerging, and these agents have the potential to overcome solid tumor heterogeneity and increase therapeutic efficacy while minimizing on‐target off‐tumor toxicity.
Gold nanoparticle-coated Pluronic-
-poly(L-lysine) nanoparticles (Pluronic-PLL@Au NPs) were synthesized via an easy one-step method and employed as carriers for the delivery of paclitaxel (PTX) in ...chemo-photothermal therapy, in which Pluronic-PLL acts as the reductant for the formation of AuNPs without the need for an additional reducing agent.
The deposition of AuNPs on the surface of Pluronic-PLL micelles and the thermal response of the system were followed via ultraviolet-visible spectroscopy and dynamic light scattering. Calcein-AM and MTT assays were used to study the cell viability of MDA-MB-231 cells treated with PTX-loaded Pluronic-PLL@Au NPs, and we then irradiated the cells with NIR light.
An obvious temperature response was observed for the Pluronic-PLL@Au NPs. Blood compatibility and
cytotoxicity assays confirmed that the Pluronic-PLL@Au NPs have excellent biocompatibility. Compared to Taxol, the PTX-loaded Pluronic-PLL@Au NPs exhibited higher cytotoxicity in MDA-MB-231 cells. All of these results and confocal laser scanning microscopy analysis results suggest that Pluronic-PLL@Au NPs greatly enhance the cellular uptake efficiency of the drug.
As confirmed by
and
studies, the combination of chemotherapy and photothermal therapy can cause more damage than chemo- or photothermal therapy did alone, demonstrating the synergistic effect of chemo-photothermal treatment. Thus, the as-prepared Pluronic-PLL@Au NPs are promising for chemo-photothermal therapy.
AZD9291 can effectively prolong survival of non‐small cell lung cancer (NSCLC) patients. Unfortunately, the mechanism of its acquired drug resistance is largely unknown. This study shows that ...autophagy and fibroblast growth factor receptor 1 signaling pathways are both activated in AZD9291 resistant NSCLC, and inhibition of them, respectively, by chloroquine (CQ) and PD173074 can synergistically reverse AZD9291 resistance. Herein, a coloaded CQ and PD173074 pH‐sensitive shell–core nanoparticles CP@NP‐cRGD is developed to reverse AZD9291 resistance in NSCLC. CP@NP‐cRGD has a high encapsulation rate and stability, and can effectively prevent the degradation of drugs in circulation process. CP@NP‐cRGD can target tumor cells by enhanced permeability and retention effect and the cRGD peptide. The pH‐sensitive CaP shell can realize lysosome escape and then release drugs successively. The combination of CP@NP‐cRGD and AZD9291 significantly induces a higher rate of apoptosis, more G0/G1 phase arrest, and reduces proliferation of resistant cell lines by downregulation of p‐ERK1/2 in vitro. CQ in CP@NP‐cRGD can block protective autophagy induced by both AZD9291 and PD173074. CP@NP‐cRGD combined with AZD9291 shows adequate tumor enrichment, low toxicity, and excellent antitumor effect in nude mice. It provides a novel multifunctional nanoparticle to overcome AZD9291 resistance for potential clinical applications.
This work develops a coloaded chloroquine and fibroblast growth factor receptor 1 (FGFR1) inhibitor pH‐sensitive shell–core nanoparticles CP@NP‐cRGD, which can significantly dual‐block autophagy and FGFR1 pathway to overcome AZD9291 resistance. CP@NP‐cRGD can ensure excellent tumor targeting ability, realize lysosomal escaping, and release drugs sequentially by pH‐sensitive CaP shell. CP@NP‐cRGD has low toxicity and long circulation time in vivo.
Multidrug resistance (MDR) is a pressing obstacle in clinical chemotherapy for breast cancer. Based on the fact that the drug efflux is an important factor in MDR, we designed a codelivery system to ...guide the drug efflux inhibitor verapamil (VRP) and the chemotherapeutic agent novantrone (NVT) synergistically into breast cancer cells to reverse MDR.
This co-delivery system consists of following components: the active targeting peptide RGD, an inorganic calcium phosphate (CaP) shell and an organic inner core. VRP and NVT were loaded into CaP shell and phosphatidylserine polyethylene glycol (PS-PEG) core of nanoparticles (NPs) separately to obtain NVT- and VRP-loaded NPs (NV@CaP-RGD). These codelivered NPs allowed VRP to prevent the efflux of NVT from breast cancer cells by competitively combining with drug efflux pumps. Additionally, NV@CaP-RGD was effectively internalized into breast cancer cells by precise delivery through the effects of the active targeting peptides RGD and EPR. The pH-triggered profile of CaP was also able to assist the NPs to successfully escape from lysosomes, leading to a greatly increased effective intracellular drug concentration.
The concurrent administration of VRP and NVT by organic/inorganic NPs is a promising therapeutic approach to reverse MDR in breast cancer.
The prostate specific membrane antigen (PSMA) is broadly overexpressed on prostate cancer (PCa) cell surfaces. In this study, we report the synthesis, characterization, in vitro binding assay, and in ...vivo magnetic resonance imaging (MRI) evaluation of PSMA targeting superparamagnetic iron oxide nanoparticles (SPIONs). PSMA-targeting polypeptide CQKHHNYLC was conjugated to SPIONs to form PSMA-targeting molecular MRI contrast agents. In vitro studies demonstrated specific uptake of polypeptide-SPIONs by PSMA expressing cells. In vivo MRI studies found that MRI signals in PSMA-expressing tumors could be specifically enhanced with polypeptide-SPION, and further Prussian blue staining showed heterogeneous deposition of SPIONs in the tumor tissues. Taken altogether, we have developed PSMA-targeting polypeptide-SPIONs that could specifically enhance MRI signal in tumor-bearing mice, which might provide a new strategy for the molecular imaging of PCa.
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