Multitarget, multiagent PLGA nanoparticles for simultaneous tumor eradication and TME remodeling in a melanoma mouse model

Drug Delivery and Translational Research, Journal Year: 2023, Volume and Issue: 14(2), P. 491 - 509

Published: Aug. 23, 2023

Abstract Despite the fact that chemoimmunotherapy has emerged as a key component in era of cancer immunotherapy, it is challenged by complex tumor microenvironment (TME) jam-packed with cellular and non-cellular immunosuppressive components. The aim this study was to design nanoparticulate system capable sufficiently accumulating spleen mediate local systemic immune responses, respectively. also aimed remodel TME. For such reasons, multi-functional polylactic-co-glycolic acid (PLGA) nanoparticles (NPs) were engineered simultaneously eradicate cells, silence tumor-associated fibroblasts (TAFs), re-educate macrophages (TAMs) using doxorubicin, losartan, metformin, These agents selected for their ability tip balance splenic cells towards immunostimulatory phenotypes. To establish TAM TAF cultures, normal incubated B16F10 melanoma cell (Mel)-derived secretome. Drug-loaded PLGA NPs prepared, characterized, tested target types. Organ distribution fluorescein-loaded evaluated mouse model melanoma. Finally, effects different combination therapy programs portrayed. vitro studies showed drug-loaded could significantly ablate nature Mel skew TAMs TAFs more favorable While vivo, proven exhibit long blood circulation time localize preferentially spleen. either metformin or losartan doxorubicin superior monotherapy, both locally systemically. However, three-agent combo produced detrimental form compromised well-being, depletion, metastasis. findings indicate potential TME remodeling means prime tumors successful chemoimmunotherapy. In addition, they shed light on importance careful use therapies necessity employing dose-reduction strategies. Graphical D-NPs doxorubicin-loaded NPs, M-NPs metformin-loaded L-NPs losartan-loaded macrophages, fibroblasts, PD-L1 programmed death ligand 1, TNF-α necrosis factor alpha, TGF-β transforming growth beta, CD206/40/86 cluster differentiation 206/40/86, α-SMA alpha-smooth muscle actin, MMPs matrix metalloproteases

Language: Английский

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Phenomic Imaging

Phenomics, Journal Year: 2023, Volume and Issue: 3(6), P. 597 - 612

Published: Nov. 3, 2023

Human phenomics is defined as the comprehensive collection of observable phenotypes and characteristics influenced by a complex interplay among factors at multiple scales. These include genes, epigenetics microscopic level, organs, microbiome mesoscopic diet environmental exposures macroscopic level. "Phenomic imaging" utilizes various imaging techniques to visualize measure anatomical structures, biological functions, metabolic processes, biochemical activities across different scales, both in vivo ex vivo. Unlike conventional medical focused on disease diagnosis, phenomic captures normal abnormal traits, facilitating detailed correlations between macro- micro-phenotypes. This approach plays crucial role deciphering phenomes. review provides an overview modalities their applications human phenomics. Additionally, it explores associations other omics disciplines, including genomics, transcriptomics, proteomics, immunomics, metabolomics. By integrating with data, such genomics metabolomics, understanding systems can be achieved. integration paves way for development new therapeutic approaches diagnostic tools.

Language: Английский

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The therapeutic effect of a novel GAPDH inhibitor in mouse model of breast cancer and efficacy monitoring by molecular imaging

Cancer Cell International, Journal Year: 2024, Volume and Issue: 24(1)

Published: May 29, 2024

Abstract Background Breast cancer is a serious threat to women’s health with high morbidity and mortality. The development of more effective therapies for the treatment breast strongly warranted. Growing evidence suggests that targeting glucose metabolism may be promising strategy. We previously identified new glyceraldehyde-3-phosphate dehydrogenase (GAPDH) inhibitor, DC-5163, which shows great potential in inhibiting tumor growth. Here, we evaluated anticancer DC-5163 cells. Methods effects on cells were investigated vitro vivo. Seahorse, uptake, lactate production, cellular ATP content assays performed examine impact glycolysis. Cell viability, colony-forming ability, cell cycle, apoptosis assessed by CCK8 assay, colony formation flow cytometry, immunoblotting respectively. activity vivo was mouse xenograft model. Results suppressed aerobic glycolysis reduced energy supply cells, thereby growth, inducing cycle arrest G0/G1 phase, increasing apoptosis. therapeutic efficacy using markedly growth without evident systemic toxicity. Micro-PET/CT scans revealed notable reduction 18 F-FDG F-FLT uptake group compared DMSO control group. Conclusions Our results suggest GAPDH inhibitor suppressing obvious side effects. PET/CT can noninvasively assess levels proliferation tumors following DC-5163.

Language: Английский

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Engineering the Tumor Immune Microenvironment through Minimally Invasive Interventions

Cancers, Journal Year: 2022, Volume and Issue: 15(1), P. 196 - 196

Published: Dec. 29, 2022

The tumor microenvironment (TME) is a unique landscape that poses several physical, biochemical, and immune barriers to anti-cancer therapies. rapidly evolving field of immuno-engineering provides new opportunities dismantle the by efficient destruction. Systemic delivery such treatments can often have limited local effects, leading unwanted offsite effects as systemic toxicity resistance. Interventional radiologists use contemporary image-guided techniques locally deliver these therapies modulate immunosuppressive TME, further accelerating death invoking better anti-tumor response. These involve intratumoral drug delivery, nanorobots, nanoparticles, implantable microdevices. Physical photodynamic therapy, electroporation, hyperthermia, hypothermia, ultrasound histotripsy, radiotherapy are also available for While interventional radiologist only manipulate there recruitments This known abscopal effect, which leads more significant anti-tumoral downstream effects. Local modern immunoengineering methods locoregional CAR-T therapy combined with checkpoint inhibitors efficaciously modulates TME. review highlights various advances technologies now change TME revolutionize oncology from minimally invasive viewpoint.

Language: Английский

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Several first-line anti-hypertensives act on fibrosarcoma progression and PD1ab blockade therapy

Journal of Orthopaedic Surgery and Research, Journal Year: 2024, Volume and Issue: 19(1)

Published: Feb. 19, 2024

Abstract Purpose Patients are typically diagnosed with both hypertension and fibrosarcoma. Medical oncologists must prescribe suitable anti-hypertensive medications while considering anti-tumor drugs. Recently, immunotherapy has become prominent in cancer treatment. Nonetheless, it is unknown what role will play immunotherapy. Methods We examined the effects of six first-line on programmed cell death protein 1 antibody (PD1ab) tumor treatment using a mouse model subcutaneous The drugs were verapamil, losartan, furosemide, spironolactone, captopril, hydrochlorothiazide (HCTZ). infiltration CD8 + T cells was by immunohistochemistry. Additionally, several vitro vivo assays used to study HCTZ human fibrosarcoma explore its mechanism. Results Verapamil suppressed growth showed an improved effect inhibition PD1ab. Captopril did not affect but brought unexpected benefit PD1ab In contrast, spironolactone furosemide no had offset therapy. Consequently, survival time mice also significantly reduced. Notably, losartan HCTZ, especially promoted weakened Consistent results observed line HT1080. determined that Solute Carrier Family 12 Member 3 (SLC12A3), known target may be principal factor underlying effect-enhancing properties through mechanism studies employing Cancer Genome Atlas (TCGA) data assays. Conclusion captopril potentiated PD1ab, whereas inhibition. Alarmingly, impaired Furthermore, we preliminarily found promote progression SLC12A3. Based this study, futher researches clinical trials should conducted future.

Language: Английский

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