Understanding the mechanism of radioresistance could help develop strategies to improve therapeutic response of patients with PDAC. The
gene is frequently mutated in pancreatic cancer. In this study, ...we investigated the role of
deficiency in pancreatic cancer cells' response to radiotherapy.
We downregulated SMAD4 expression with
siRNA or
shRNA and overexpressed SMAD4 in
mutant pancreatic cancer cells followed by clonogenic survival assay to evaluate their effects on cell radioresistance. To study the mechanism of radioresistance, the effects of
loss on reactive oxygen species (ROS) and autophagy were determined by flow cytometry and immunoblot analysis, respectively. Furthermore, we measured radioresistance by clonogenic survival assay after treatment with autophagy inhibitor (Chloroquine) and ROS inhibitor (N-acetyl-l-cysteine) in
-depleted pancreatic cancer cells. Finally, the effects of
on radioresistance were also confirmed in an orthotopic tumor model derived from
-depleted Panc-1 cells.
-depleted pancreatic cancer cells were more resistant to radiotherapy based on clonogenic survival assay. Overexpression of wild-type SMAD4 in
-mutant cells rescued their radiosensitivity. Radioresistance mediated by
depletion was associated with persistently higher levels of ROS and radiation-induced autophagy. Finally,
depletion induced
radioresistance in Panc-1-derived orthotopic tumor model (
= 0.038). More interestingly, we observed that the protein level of SMAD4 is inversely correlated with autophagy in orthotopic tumor tissue samples.
Our results demonstrate that defective
is responsible for radioresistance in pancreatic cancer through induction of ROS and increased level of radiation-induced autophagy.
.
Immunosuppressive tumor microenvironment (TME) and ascites-derived spheroids in ovarian cancer (OC) facilitate tumor growth and progression, and also pose major obstacles for cancer therapy. The ...molecular pathways involved in the OC-TME interactions, how the crosstalk impinges on OC aggression and chemoresistance are not well-characterized. Here, we demonstrate that tumor-derived UBR5, an E3 ligase overexpressed in human OC associated with poor prognosis, is essential for OC progression principally by promoting tumor-associated macrophage recruitment and activation via key chemokines and cytokines. UBR5 is also required to sustain cell-intrinsic β-catenin-mediated signaling to promote cellular adhesion/colonization and organoid formation by controlling the p53 protein level. OC-specific targeting of UBR5 strongly augments the survival benefit of conventional chemotherapy and immunotherapies. This work provides mechanistic insights into the novel oncogene-like functions of UBR5 in regulating the OC-TME crosstalk and suggests that UBR5 is a potential therapeutic target in OC treatment for modulating the TME and cancer stemness.
The tumor-promoting potential of CCL5 has been proposed but remains poorly understood. We demonstrate here that an autocrine CCL5-CCR5 axis is a major regulator of immunosuppressive myeloid cells ...(IMC) of both monocytic and granulocytic lineages. The absence of the autocrine CCL5 abrogated the generation of granulocytic myeloid-derived suppressor cells and tumor-associated macrophages. In parallel, enhanced maturation of intratumoral neutrophils and macrophages occurred in spite of tumor-derived CCL5. The refractory nature of
-null myeloid precursors to tumor-derived CCL5 was attributable to their persistent lack of membrane-bound CCR5. The changes in the
-null myeloid compartment subsequently resulted in increased tumor-infiltrating cytotoxic CD8
T cells and decreased regulatory T cells in tumor-draining lymph nodes. An analysis of human triple-negative breast cancer specimens demonstrated an inverse correlation between "immune CCR5" levels and the maturation status of tumor-infiltrating neutrophils as well as 5-year-survival rates. Targeting the host CCL5 in bone marrow via nanoparticle-delivered expression silencing, in combination with the CCR5 inhibitor Maraviroc, resulted in strong reductions of IMC and robust antitumor immunities. Our study suggests that the myeloid CCL5-CCR5 axis is an excellent target for cancer immunotherapy.
.
Regenerated silk fibroin (SF) is a natural biomacromolecule with excellent biocompatible and biodegradable properties. In this study, cyclic pentapeptide cRGDfk and Chlorin e6 (Ce6) were conjugated ...to SF polypeptides, and genipin was used to prepare 5-fluorouracil (5-FU) doped SF-based nanoparticles (NPs). The photodynamic therapy (PDT) potential and active targeting properties were systematically investigated in αvβ3 integrin receptor over-expressed MGC-803 cells in vitro. The results revealed that treatment with the multifunctional SF-based NPs and PDT, high level of reactive oxygen species (ROS) and cell death can be induced in MGC-803 cells. Combine with PDT, the in vivo antitumor effect of the SF-based NPs was evaluated in gastric cancer xenograft mice model. The results demonstrated that the SF-based NPs had ideal active tumor targeting property and the tumor burden can be reduced noticeably. Furthermore, the organs of mice in SF NPs treatment groups did not show obvious toxicity, demonstrating good biocompatibility and security profiles of SF NPs in vivo. Overall, our results suggest that the SF-based NPs are promising drug delivery carriers, together with PDT, the multimodality therapy could be potential regimen in future clinical cancer treatment.
The cRGDfk and Chlorin e6 conjugated Silk fibroin (SF) based nanoparticles (SF NPs) were fabricated for targeted drug (5-FU) delivery and photodynamic therapy (PDT). The SF NPs manifested sustained release, active tumor cell targeting, perfect PDT potentials, and reduced the tumor burden greatly in vivo with excellent biocompatibility and safety. Display omitted
•cRGDfk and Chlorin e6 conjugated SF-based NPs were fabricated for targeted drug delivery and photodynamic therapy (PDT).•The SF-based NPs manifested sustained release, active tumor cell targeting, and perfect PDT potentials in MGC-803 cells.•Together with PDT, the SF-based NPs reduced the tumor burden greatly with excellent biocompatibility and safety in vivo.
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•Both Kupffer cell depletion and pegylation reduce liposome accumulation in the liver.•Pegylation is a more effective strategy for preventing liposome uptake in the liver.•Several ...cell types may be involved in liposome clearance by the liver.•Further research is necessary to identify the major cell types involved.
The liver is a major barrier for site-specific delivery of systemically injected nanoparticles, as up to 90% of the dose is usually captured by this organ. Kupffer cells are thought to be the main cellular component responsible for nanoparticle accumulation in the liver. These resident macrophages form part of the mononuclear phagocyte system, which recognizes and engulfs foreign bodies in the circulatory system. In this study, we have compared two strategies for reducing nanoparticle accumulation in the liver, in order to investigate the specific contribution of Kupffer cells. Specifically, we have performed a comparison of the capability of pegylation and Kupffer cell depletion to reduce liposome accumulation in the liver. Pegylation reduces nanoparticle interactions with all types of cells and can serve as a control for elucidating the role of specific cell populations in liver accumulation. The results indicate that liposome pegylation is a more effective strategy for avoiding liver uptake compared to depletion of Kupffer cells, suggesting that nanoparticle interactions with other cells in the liver may also play a contributing role. This study highlights the need for a more complete understanding of factors that mediate nanoparticle accumulation in the liver and for the exploration of microenvironmental modulation strategies for reducing nanoparticle-cell interactions in this organ.
Safety of Nanoparticles in Medicine Wolfram, Joy; Zhu, Motao; Yang, Yong ...
Current drug targets,
01/2015, Volume:
16, Issue:
14
Journal Article
Peer reviewed
Open access
Nanomedicine involves the use of nanoparticles for therapeutic and diagnostic purposes. During the past two decades, a growing number of nanomedicines have received regulatory approval and many more ...show promise for future clinical translation. In this context, it is important to evaluate the safety of nanoparticles in order to achieve biocompatibility and desired activity. However, it is unwarranted to make generalized statements regarding the safety of nanoparticles, since the field of nanomedicine comprises a multitude of different manufactured nanoparticles made from various materials. Indeed, several nanotherapeutics that are currently approved, such as Doxil and Abraxane, exhibit fewer side effects than their small molecule counterparts, while other nanoparticles (e.g. metallic and carbon-based particles) tend to display toxicity. However, the hazardous nature of certain nanomedicines could be exploited for the ablation of diseased tissue, if selective targeting can be achieved. This review discusses the mechanisms for molecular, cellular, organ, and immune system toxicity, which can be observed with a subset of nanoparticles. Strategies for improving the safety of nanoparticles by surface modification and pretreatment with immunomodulators are also discussed. Additionally, important considerations for nanoparticle safety assessment are reviewed. In regards to clinical application, stricter regulations for the approval of nanomedicines might not be required. Rather, safety evaluation assays should be adjusted to be more appropriate for engineered nanoparticles.
Nanoplatforms for mRNA Therapeutics Meng, Chaoyang; Chen, Zhe; Li, Gang ...
Advanced therapeutics,
January 2021, Volume:
4, Issue:
1
Journal Article
Peer reviewed
mRNA‐based therapeutics are a unique class of drugs for treatment of human diseases. Since in vitro transcribed mRNA molecules have relatively low stability and their surface charge prevents them ...from direct cell entry, they need to be packaged into specially designed delivery platforms to exert their activities. Multiple nanotechnology‐based delivery platforms have been developed for mRNA delivery, such as polymer‐based polyplex, lipid‐based lipoplex, and lipid‐coated polymer‐based lipopolyplex. In this review, an overview of the nanoplatforms for mRNA delivery is provided. A number of applications in biotechnology including cell reprogramming and gene editing are also described. In addition, their clinical translational potential for protein replacement therapy and for infectious disease and cancer treatment is introduced.
mRNA‐based therapeutics are a unique class of drugs for human disease treatment. Multiple types of delivery platforms have been developed to deliver mRNA molecules into target cells, to promote mRNA translation, and to ensure drug efficacy. A number of mRNA‐based therapies are at different stages of clinical evaluation for treatment of cancer and infectious diseases, including the globally rampant COVID‐19.
Site-specific localization is critical for improving the therapeutic efficacy and safety of drugs. Nanoparticles have emerged as promising tools for localized drug delivery. However, over 90% of ...systemically injected nanocarriers typically accumulate in the liver and spleen due to resident macrophages that form the mononuclear phagocyte system. In this study, the clinically approved antimalarial agent chloroquine was shown to reduce nanoparticle uptake in macrophages by suppressing endocytosis. Pretreatment of mice with a clinically relevant dose of chloroquine substantially decreased the accumulation of liposomes and silicon particles in the mononuclear phagocyte system and improved tumoritropic and organotropic delivery. The novel use of chloroquine as a macrophage-preconditioning agent presents a straightforward approach for addressing a major barrier in nanomedicine. Moreover, this priming strategy has broad applicability for improving the biodistribution and performance of particulate delivery systems. Ultimately, this study defines a paradigm for the combined use of macrophage-modulating agents with nanotherapeutics for improved site-specific delivery.
The outbreak of new coronavirus disease (COVID-19) has quickly spread all over the world. Real time reverse transcriptase polymerase chain reaction (rRT-PCR) for nucleic acid detection has become the ...standard method for clinical diagnosis of COVID-19 infection. But these rRT-PCR tests have many inherent limitations, and carry a high false negative rate. It is an urgent to develop a method to accurately identify the vast infected patients and asymptomatic viral carriers from the population. In this article, we present the principle and procedure of developing a colloidal gold immunochromatographic assay (GICA) for rapid detection of COVID-19-specific antibodies. The detection kit can be used to detect immunoglobulin M (IgM) and IgG of COVID-19 in human blood samples within 15 minutes, and to identify different stages of viral infection. Test results can be digitalized using an office scanner and a FiJi software with appropriate confidence interval (CI) setting. Based on analysis from 375 samples, we calculated that overall sensitivity and specificity of the assay were 95.85% and 97.47%, respectively. Compared with rRT-PCR, this assay has many advantages including convenience and rapid detection. The detection kit can be widely used in hospitals, clinics and laboratories for rapid screening of both symptomatic and asymptomatic COVID-19 carriers in large scale.
The preparation principle and the result interpretation of COVID-19 antibody rapid detection strip.
E-selectin is a surface marker of endothelial cell (EC) inflammation, one of the hallmarks of atherogenesis. Thus, we tested the hypothesis that delivery of microRNA (miR)-146a and miR-181b with an ...E-selectin-targeting multistage vector (ESTA-MSV) to inflamed endothelium covering atherosclerotic plaques inhibits atherosclerosis. Cy5-conjugated miR-146a and miR-181b were packaged in polyethylene glycol-polyethyleneimine (PEG/PEI) nanoparticles and loaded into ESTA-MSV microparticles. Both miRs were downregulated in tumor necrosis factor (TNF)-α-treated ECs. Transfection of TNF-α-treated mouse aortas and cultured ECs with miRs was more efficient with ESTA-MSV than with the PEG/PEI. Likewise, miR-146a/-181b packaged in ESTA-MSV efficiently suppressed the chemokines, CCL2, CCL5, CCL8, and CXCL9, and monocyte adhesion to ECs. Complementary in vivo tests were conducted in male apolipoprotein E-deficient mice fed a Western diet and injected intravenously with the particles prepared as above biweekly for 12 weeks. Treatment with miRs packaged in ESTA-MSV but not in PEG/PEI reduced atherosclerotic plaque size. Concurrently, vascular inflammation markers, including macrophages in aortic root lesions and chemokine expression in aortic tissues were reduced while the vascular smooth muscle cells and collagen increased in plaques from ESTA-MSV/miRs-treated vs. vehicle-treated mice. Our data supported our hypothesis that ESTA-MSV microparticle-mediated delivery of miR-146a/-181b ameliorates endothelial inflammation and atherosclerosis.
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