Targeting Signaling Pathways of Hyaluronic Acid and Integrin Receptors by Synergistic Combination Nanocomposites Inhibits Systemic Metastases and Primary Triple Negative Breast Cancer

Zhang, Tian; Fu, Chaoping; Alradwan, Ibrahim; Yen, TinYo; Lip, HoYin; Cai, Ping; Rauth, Andrew M.; Zhang, Liming; Wu, Xiao Yu

doi:10.1002/adtp.202100022

Cited by 6 publications

(6 citation statements)

References 48 publications

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“…Median effect analysis was also conducted to construct the median effect plot [ 40 , 41 ] for the identification of drug synergism. Briefly, dose–effect curves were constructed based on previous MTT assay results ( Figure S8A,B ).…”

Section: Resultsmentioning

confidence: 99%

Polyethylenimine-Conjugated Hydroxyethyl Cellulose for Doxorubicin/Bcl-2 siRNA Co-Delivery Systems

Park

Kim

2023

Pharmaceutics

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Hydroxyethyl cellulose (HEC), widely known for its biocompatibility and water solubility, is a polysaccharide with potential for pharmaceutical applications. Here, we synthesized polyethylenimine2k (PEI2k)-conjugated hydroxyethyl cellulose (HECP2k) for doxorubicin/Bcl-2 siRNA co-delivery systems. HECP2ks were synthesized by reductive amination of PEI2k with periodate-oxidized HEC. The synthesis of the polymers was characterized using 1H NMR, 13C NMR, primary amine quantification, FT-IR, and GPC. Via agarose gel electrophoresis and Zeta-sizer measurement, it was found that HECP2ks condensed pDNA to positively charged and nano-sized complexes (100–300 nm, ~30 mV). The cytotoxicity of HECP2ks was low and HECP2k 10X exhibited higher transfection efficiency than PEI25k even in serum condition, showing its high serum stability from ethylene oxide side chains. Flow cytometry analysis and confocal laser microscopy observation verified the superior cellular uptake and efficient endosome escape of HECP2k 10X. HECP2k 10X also could load Dox and Bcl-2 siRNA, forming nano-particles (HECP2k 10X@Dox/siRNA). By median effect analysis and annexin V staining analysis, it was found that HECP2k 10X@Dox/siRNA complexes could cause synergistically enhanced anti-cancer effects to cancer cells via induction of apoptosis. Consequently, it was concluded that HECP2k possesses great potential as a promising Dox/Bcl-2 siRNA co-delivery carrier.

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Section: Resultsmentioning

confidence: 99%

Polyethylenimine-Conjugated Hydroxyethyl Cellulose for Doxorubicin/Bcl-2 siRNA Co-Delivery Systems

Park

Kim

2023

Pharmaceutics

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“…To target multiple pathways, Zhang et al developed a iRGD−oHA−DOX PLN system with a synergistic ratio of DOX/oHA = 1:4. 137 The intracellular release of oHA showed antimigration and anti-invasion effects via its antagonistic effects on CD44−(HA) interactionmediated metastasis signaling pathways, especially the interaction with the receptor for hyaluronan mediated motility (RHAAM) and downregulation of the phospho-extracellular signal-regulated kinase (p-ERK). As compared to the free DOX and oHA, the iRGD−oHA−DOX PLN substantially reduced tumor burden and prevented spontaneous metastasis to the lungs and lymph nodes in a TNBC mouse model.…”

Section: Multitargeted and Intracellularlymentioning

confidence: 99%

“…As compared to the free DOX and oHA, the iRGD−oHA−DOX PLN substantially reduced tumor burden and prevented spontaneous metastasis to the lungs and lymph nodes in a TNBC mouse model. 137 4.2. Intracellular Cascade Delivery and Activation of Drugs by NPs.…”

Section: Multitargeted and Intracellularlymentioning

confidence: 99%

“…TNBC is known for its aggressive growth, drug resistance, and high incidence of metastasis. To target multiple pathways, Zhang et al developed a iRGD–oHA–DOX PLN system with a synergistic ratio of DOX/oHA = 1:4 . The intracellular release of oHA showed antimigration and anti-invasion effects via its antagonistic effects on CD44–(HA) interaction-mediated metastasis signaling pathways, especially the interaction with the receptor for hyaluronan mediated motility (RHAAM) and downregulation of the phospho-extracellular signal-regulated kinase (p-ERK).…”

Section: Multitargeted and Intracellularly Activated Nanomedicinementioning

confidence: 99%

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Advances in Nanomedicine Design: Multidisciplinary Strategies for Unmet Medical Needs

Ahmed

Liu

et al. 2022

Mol. Pharmaceutics

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Globally, a rising burden of complex diseases takes a heavy toll on human lives and poses substantial clinical and economic challenges. This review covers nanomedicine and nanotechnology-enabled advanced drug delivery systems (DDS) designed to address various unmet medical needs. Key nanomedicine and DDSs, currently employed in the clinic to tackle some of these diseases, are discussed focusing on their versatility in diagnostics, anticancer therapy, and diabetes management. Firsthand experiences from our own laboratory and the work of others are presented to provide insights into strategies to design and optimize nanomedicine-and nanotechnology-enabled DDS for enhancing therapeutic outcomes. Computational analysis is also briefly reviewed as a technology for rational design of controlled release DDS. Further explorations of DDS have illuminated the interplay of physiological barriers and their impact on DDS. It is demonstrated how such delivery systems can overcome these barriers for enhanced therapeutic efficacy and how new perspectives of next-generation DDS can be applied clinically.

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“…Principally, RGD-based peptides containing the triple amino acid sequence Arg-Gly-Asp (e.g., iRGD, a novel cyclic peptide composed of nine amino acids including an RGD motif) have been widely used for producing polymer-based drug delivery platforms. They present precise targeting toward cell membrane receptors (i.e., α v β 3 and α v β 5 integrins) that are overexpressed by several cancerous tumors, including the GBM form [ 15 , 16 , 17 , 18 ]. This approach permits optimizing the efficiency of cancer therapies by lowering drug concentrations and surpassing one of the main challenges in nano-oncology research associated with undesired side effects, including the non-specific attack of the chemotherapeutic molecules on normal cells when using conventional treatments [ 8 , 9 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

Bioengineered Carboxymethylcellulose–Peptide Hybrid Nanozyme Cascade for Targeted Intracellular Biocatalytic–Magnetothermal Therapy of Brain Cancer Cells

et al. 2022

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Glioblastoma remains the most lethal form of brain cancer, where hybrid nanomaterials biofunctionalized with polysaccharide peptides offer disruptive strategies relying on passive/active targeting and multimodal therapy for killing cancer cells. Thus, in this research, we report for the first time the rational design and synthesis of novel hybrid colloidal nanostructures composed of gold nanoparticles stabilized by trisodium citrate (AuNP@TSC) as the oxidase-like nanozyme, coupled with cobalt-doped superparamagnetic iron oxide nanoparticles stabilized by carboxymethylcellulose ligands (Co-MION@CMC) as the peroxidase-like nanozyme. They formed inorganic–inorganic dual-nanozyme systems functionalized by a carboxymethylcellulose biopolymer organic shell, which can trigger a biocatalytic cascade reaction in the cancer tumor microenvironment for the combination of magnetothermal–chemodynamic therapy. These nanoassemblies were produced through a green aqueous process under mild conditions and chemically biofunctionalized with integrin-targeting peptide (iRDG), creating bioengineered nanocarriers. The results demonstrated that the oxidase-like nanozyme (AuNP) was produced with a crystalline face-centered cubic nanostructure, spherical morphology (diameter = 16 ± 3 nm), zeta potential (ZP) of −50 ± 5 mV, and hydrodynamic diameter (DH) of 15 ± 1 nm. The peroxide-like nanostructure (POD, Co-MION@CMC) contained an inorganic crystalline core of magnetite and had a uniform spherical shape (2R = 7 ± 1 nm) which, summed to the contribution of the CMC shell, rendered a hydrodynamic diameter of 45 ± 4 nm and a negative surface charge (ZP = −41 ± 5 mV). Upon coupling both nanozymes, water-dispersible colloidal supramolecular vesicle-like organic–inorganic nanostructures were produced (AuNP//Co-MION@CMC, ZP = −45 ± 4 mV and DH = 28 ± 3 nm). They confirmed dual-nanozyme cascade biocatalytic activity targeted by polymer–peptide conjugates (AuNP//Co-MION@CMC_iRGD, ZP = −29 ± 3 mV and DH = 60 ± 4 nm) to kill brain cancer cells (i.e., bioenergy “starvation” by glucose deprivation and oxidative stress through reactive oxygen species generation), which was boosted by the magneto-hyperthermotherapy effect when submitted to the alternating magnetic field (i.e., induced local thermal stress by “nanoheaters”). This groundwork offers a wide avenue of opportunities to develop innovative theranostic nanoplatforms with multiple integrated functionalities for fighting cancer and reducing the harsh side effects of conventional chemotherapy.

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Targeting Signaling Pathways of Hyaluronic Acid and Integrin Receptors by Synergistic Combination Nanocomposites Inhibits Systemic Metastases and Primary Triple Negative Breast Cancer

Cited by 6 publications

References 48 publications

Polyethylenimine-Conjugated Hydroxyethyl Cellulose for Doxorubicin/Bcl-2 siRNA Co-Delivery Systems

Polyethylenimine-Conjugated Hydroxyethyl Cellulose for Doxorubicin/Bcl-2 siRNA Co-Delivery Systems

Advances in Nanomedicine Design: Multidisciplinary Strategies for Unmet Medical Needs

Bioengineered Carboxymethylcellulose–Peptide Hybrid Nanozyme Cascade for Targeted Intracellular Biocatalytic–Magnetothermal Therapy of Brain Cancer Cells

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