Regulation of pancreatic cancer microenvironment by an intelligent gemcitabine@nanogel system via in vitro 3D model for promoting therapeutic efficiency

Chen, Di; Zhu, Xiaofei; Tao, Wanru; Kong, Yan Yan; Huag, Yong; Zhang, Yajun; Liu, Ri; Jiang, Lingong; Tang, Ying; Yu, Haiyan; Hao, Qiang; Yang, Xiangqun; Zou, Hao; Chen, Jianming; Lü, Ying; Zhang, Huojun; Li, Wei

doi:10.1016/j.jconrel.2020.06.001

Cited by 24 publications

(15 citation statements)

References 37 publications

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“…Toward accelerating new therapies preclinical screening, researchers have been actively developing evermore advanced and biomimetic 3D PDAC in vitro testing models encompassing only monotypic cancer cells agglomerates or heterotypic cancer‐stromal co‐cultured 3D microtumors, matured in both static and dynamic tumor‐on‐a‐chip platforms. [ 12–16 ] However, despite extensive efforts and the numerous models developed, to date, the recapitulation of PDAC bioarchitecture has yet to be demonstrated. In fact, most models reported to date still randomly mix cancer and stromal cells during 3D agglomerates assembly, a highly heterogeneous and uncontrolled process, ultimately falling short on representing in vitro the native cellular spatial distribution found in human pancreatic cancer.…”

Section: Introductionmentioning

confidence: 99%

Stratified 3D Microtumors as Organotypic Testing Platforms for Screening Pancreatic Cancer Therapies

et al. 2021

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Cancer‐associated pancreatic stellate cells installed in periacinar/periductal regions are master players in generating the characteristic biophysical shield found in pancreatic ductal adenocarcinoma (PDAC). Recreating this unique PDAC stromal architecture and its desmoplastic microenvironment in vitro is key to discover innovative treatments. However, this still remains highly challenging to realize. Herein, organotypic 3D microtumors that recapitulate PDAC‐stroma spatial bioarchitecture, as well as its biomolecular, metabolic, and desmoplastic signatures, are bioengineered. Such newly engineered platforms, termed stratified microenvironment spheroid models – STAMS – mimic the spatial stratification of cancer‐stromal cells, exhibit a reproducible morphology and sub‐millimeter size. In culture, 3D STAMS secrete the key molecular biomarkers found in human pancreatic cancer, namely TGF‐β, FGF‐2, IL‐1β, and MMP‐9, among others. This is accompanied by an extensive desmoplastic reaction where collagen and glycosaminoglycans (GAGs) de novo deposition is observed. These stratified models also recapitulate the resistance to various chemotherapeutics when compared to standard cancer–stroma random 3D models. Therapeutics resistance is further evidenced upon STAMS inclusion in a tumor extracellular matrix (ECM)‐mimetic hydrogel matrix, reinforcing the importance of mimicking PDAC‐stroma bioarchitectural features in vitro. The 3D STAMS technology represents a next generation of biomimetic testing platforms with improved potential for advancing high‐throughput screening and preclinical validation of innovative pancreatic cancer therapies.

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Section: Introductionmentioning

confidence: 99%

Stratified 3D Microtumors as Organotypic Testing Platforms for Screening Pancreatic Cancer Therapies

et al. 2021

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“…Aggregated JC‐1 appears to be red with high potential, indicating faulty membrane permeability; while monomeric JC‐1 appears to be green with low potential indicating good membrane permeability. [ 39 , 43 ] Here, the outer membrane of the mitochondria of MDA‐MB‐231 was stained with JC‐1 (10 µg mL −1 ) and analyzed using CLSM (Figure 3C ). CLSM images display obvious green color in groups treated by GNRs, indicating high MOMP.…”

Section: Resultsmentioning

confidence: 99%

Death Pathways of Cancer Cells Modulated by Surface Molecule Density on Gold Nanorods

et al. 2021

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Necrosis induces strong inflammation with undesirable implications in clinics compared with apoptosis. Fortunately, the switch between necrosis and apoptosis could be realized by tailoring the appropriate structural properties of gold nano rods (GNRs) that could precisely modulate cell death pathways. Herein, the intracellular interaction between GNRs and organelles is monitored and it is found that lysosomes dominates necrosis/apoptosis evoking. Then the surface molecule density of GNRs, which is first defined as 𝝆 surf. molecule (N surf. molecules /(a × 𝝅 × Diameter × Length)), mediates lysosome activities as the membrane permeabilization (LMP), the Cathepsin B and D release, the cross-talk between lysosome and different organelles, which selectively evokes apoptosis or necrosis and the production of TNF-𝜶 from macrophages. GNRs with small 𝝆 surf. molecule mainly induce apoptosis, while with large 𝝆 surf. molecule they greatly contribute to necrosis. Interestingly, necrosis can be suppressed by GNRs with higher 𝝆 surf. molecule due to the overexpression of key protease caspase 8, which cleaves the RIP1-RIP3 complex and activates caspase 3 followed by necrosis to apoptosis transition. This investigation indicates that the 𝝆 surf. molecule greatly affects the utility of nanomaterials and different structural properties of nanomaterials have different implications in clinics.

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“…Nanocarrier-based gemcitabine delivery systems are able to enhance the bioavailability of gemcitabine since they can selectively accumulate in tumor sites by the EPR effect [47] , [48] , [49] . Besides, they can carry gemcitabine into the cancer cells by endocytosis rather than through nucleoside transports that are few in drug-resistant cells.…”

Section: Nano-drug Strategies Using Nanocarriersmentioning

confidence: 99%

Emerging pro-drug and nano-drug strategies for gemcitabine-based cancer therapy

Han

Zhong

et al. 2022

Asian Journal of Pharmaceutical Sciences

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Regulation of pancreatic cancer microenvironment by an intelligent gemcitabine@nanogel system via in vitro 3D model for promoting therapeutic efficiency

Cited by 24 publications

References 37 publications

Stratified 3D Microtumors as Organotypic Testing Platforms for Screening Pancreatic Cancer Therapies

Stratified 3D Microtumors as Organotypic Testing Platforms for Screening Pancreatic Cancer Therapies

Death Pathways of Cancer Cells Modulated by Surface Molecule Density on Gold Nanorods

Emerging pro-drug and nano-drug strategies for gemcitabine-based cancer therapy

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