Synthetically lethal nanoparticles for treatment of endometrial cancer

Ebeid, Kareem; Meng, Xiangjun; Thiel, Kristina W.; Vu, Anh Dung; Geary, Sean M.; Morris, Angie S.; Pham, Erica L.; Wongrakpanich, Amaraporn; Chhonker, Yashpal S.; Murry, Daryl J.; Leslie, Kimberly K.; Salem, Aliasger K.

doi:10.1038/s41565-017-0009-7

Cited by 59 publications

(45 citation statements)

References 49 publications

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“…Efficient aerosol delivery systems that consider the aerodynamic diameter of particles, and the amount of DNA deposited at the target site are critical to the development of effective approaches to gene delivery to the lung (10). Polymeric particles have gained interest as potential drug and gene delivery systems because they offer protection of the cargo from degradation, increase drug circulation time, can provide sustained release of the cargo over time, are highly tunable, and, in many cases, are biocompatible (11)(12)(13)(14)(15)(16)(17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

Tunable Properties of Poly-DL-Lactide-Monomethoxypolyethylene Glycol Porous Microparticles for Sustained Release of Polyethylenimine-DNA Polyplexes

et al. 2019

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Direct pulmonary delivery is a promising step in developing effective gene therapies for respiratory disease. Gene therapies can be used to treat the root cause of diseases, rather than just the symptoms. However, developing effective therapies that do not cause toxicity and that successfully reach the target site at therapeutic levels is challenging. We have developed a polymer-DNA complex utilizing polyethylene imine (PEI) and DNA, which was then encapsulated into poly(lactic acid)-co-monomethoxy poly(ethylene glycol) (PLA-mPEG) microparticles via double emulsion, solvent evaporation. Then, the resultant particle size, porosity, and encapsulation efficiency were measured as a function of altering preparation parameters. Microsphere formation was confirmed from scanning electron micrographs and the aerodynamic particle diameter was measured using an aerodynamic particle sizer. Several formulations produced particles with aerodynamic diameters in the 0-5 μm range despite having larger particle diameters which is indicative of porous particles. Furthermore, these aerodynamic diameters correspond to high deposition within the airways when inhaled and the measured DNA content indicated high encapsulation efficiency. Thus, this formulation provides promise for developing inhalable gene therapies.

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Section: Introductionmentioning

confidence: 99%

Tunable Properties of Poly-DL-Lactide-Monomethoxypolyethylene Glycol Porous Microparticles for Sustained Release of Polyethylenimine-DNA Polyplexes

et al. 2019

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“…Many studies indicated that pristimerin is a substrate to P-gp, therefore loading pristimerin in NPs containing TPGS would enhance its intracellular accumulation through inhibiting its efflux [39]. Our lab has recently demonstrated that loading a substrate to P-gp efflux transporter in NPs prepared with TPGS significantly improved the substrates intracellular accumulation once compared to its soluble form [15]. Regarding cancer treatment, nanoparticles <200 nm in diameter offer superior accumulation at the tumor site due to the enhanced permeability and retention (EPR) effect.…”

Section: Discussionmentioning

confidence: 97%

“…To enhance drug solubility, stability and accumulation in the tumor, a nanoparticle formulation was used to deliver pristimerin to tumors in vivo [15]. Nanoparticles have been extensively utilized for delivering therapeutic and diagnostic agents.…”

Section: Discussionmentioning

confidence: 99%

“…Pristimerin-loaded Poly (DL-lactide-co-glycolide) (PLGA) nanoparticles were prepared using the nanoprecipitation method as described previously [15]. Briefly, 2 mg of pristimerin and 20 mg of 75:25 Poly (DL-lactide-co-glycolide) (Lactel Absorbable Polymers, Birmingham, AL) were dissolved in 3.4 ml of acetone, sonicated for 10 min (Branson® 5200), and then mixed with 0.6 ml of 97% ethanol.…”

Section: Preparation Of Pristimerin-loaded Nanoparticlesmentioning

confidence: 99%

“…We therefore used a nanoparticle-based delivery approach to improve the pharmacokinetics and therapeutic efficacy of pristimerin. Pristimerin was loaded into PLGA nanoparticles based on our previous studies [15]. The amount of pristimerin-loaded nanoparticles was quantified by HPLC.…”

Section: Quantification and Characterization Of Pristimerin-loaded Plmentioning

confidence: 99%

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MTDH/AEG-1 downregulation using pristimerin-loaded nanoparticles inhibits Fanconi anemia proteins and increases sensitivity to platinum-based chemotherapy

Areecheewakul

et al. 2019

Gynecologic Oncology

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h i g h l i g h t sEndometrial cancer patients with high copy number of MTDH show poor outcome.Inhibition MTDH increases DNA damage induced g-H2Ax foci formation and sensitivity to cisplatin.MTDH binds with mRNAs encoding for FANCD2 and FANCI. Pristimerin-loaded nanoparticles inhibit MTDH, FANCD2 and FANCI to increase sensitivity to cisplatin. a b s t r a c tObjective: Platinum compounds have been widely used as a primary treatment for many types of cancer. However, resistance is the major cause of therapeutic failure for patients with metastatic or recurrent disease, thus highlighting the need to identify novel factors driving resistance to Platinum compounds. Metadherin (MTDH, also known as AEG-1 and LYRIC), located in a frequently amplified region of chromosome 8, has been consistently associated with resistance to chemotherapeutic agents, though the precise mechanisms remain incompletely defined.Methods: The mRNA of FANCD2 and FANCI was pulled down by RNA-binding protein immunoprecipitation. Pristimerin-loaded nanoparticles were prepared using the nanoprecipitation method. Immunocompromised mice bearing patient-derived xenograft tumors were treated with pristimerinloaded nanoparticles, cisplatin and a combination of the two.Results: MTDH, through its recently discovered role as an RNA binding protein, regulates expression of FANCD2 and FANCI, two components of the Fanconi anemia complementation group (FA) that play critical roles in interstrand crosslink damage induced by platinum compounds. Pristimerin, a quinonemethide triterpenoid extract from members of the Celastraceae family used to treat inflammation in traditional Chinese medicine, significantly decreased MTDH, FANCD2 and FANCI levels in cancer cells, thereby restoring sensitivity to platinum-based chemotherapy. Using a patient-derived xenograft model of endometrial cancer, we discovered that treatment with pristimerin in a novel nanoparticle formulation markedly inhibited tumor growth when combined with cisplatin.Conclusions: MTDH is involved in post-transcriptional regulation of FANCD2 and FANCI. Pristimerin can increase sensitivity to platinum-based agents in tumors with MTDH overexpression by inhibiting the FA pathway.

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Precise Subcellular Organelle Targeting for Boosting Endogenous‐Stimuli‐Mediated Tumor Therapy

Zhen

Wang

et al. 2021

Advanced Materials

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to their noninvasive and specific treatment modality from selective irradiation. [1b] However, external energy, such as light, ionizing radiation or ultrasound, is required in these therapies, which obstructs their further development due to the limited penetration depth of the laser, safety concerns of radiation, therapeutic resistance and spatio-temporal constraints of some specific equipments. In-depth exploiting the differences between the tumor microenvironment (TME) and normal organs provides an alternative way that without specific devices. Take full advantage of the TME, endogenousstimuli-mediated therapy is a novel concept in tumor treatment.The TME, mainly composed of tumor cells, vessels, lymphatic vessels, immune cells, fibroblasts, and extracellular matrix (ECM), [4] which provides a suitable environment for survival, division, angiogenesis, and metastasis of tumor cells. During the growth of tumor tissue, some regions are hypoxic [5] due to abnormal vascularization and inferior blood accommodation. [6] Normal cells can decompose glucose into pyruvate through glycolysis in the cytoplasm under normoxic conditions and the generated pyruvate is transported to the mitochondria and further decomposed into carbon dioxide, [7] which is known as tricarboxylic acid cycle (TCA). In hypoxic tumor tissues, the TCA pathway is restricted due to the insufficiency of oxygen supply. Instead, pyruvate is reduced to lactic acid to produce energy with much lower efficiency. This process on the one hand increases the consumption of glucose and pyruvate, and on the other hand increases acidity of the extracellular TME (pH value: 6.5-6.8) due to the secreted lactic acid. [8] Another noteworthy property of the TME is the increased level of reactive oxygen species (ROS). [9] The term ROS mainly includes hydrogen peroxide (H 2 O 2 ), singlet oxygen ( 1 O 2 ), hydroxyl radical (•OH), superoxide (•O 2 − ), ozone, lipid peroxides, hypochlorous acid, which often determines many biological responses and metabolic processes within the tumor [10] directly and/or indirectly. [11] Increased expression of ROS-scavenging enzymes and antioxidant molecules could balance the high levels of ROS, which may contribute to the accommodative response of tumor cells to many therapies. [12] For example, glutathione (GSH) plays a vital role in the protection of cells against lectrophilic and oxidative stress as it is engaged in the metabolism and detoxification process of many cytotoxic and carcinogenic species with the oxidation of GSH to its oxidized Though numerous external-stimuli-triggered tumor therapies, including phototherapy, radiotherapy, and sonodynamic therapy have made great progress in cancer therapy, the low penetration depth of the laser, safety concerns of radiation, the therapeutic resistance, and the spatio-temporal constraints of the specific equipment restrict their convenient clinical applications. What is more, the inherent physiological barriers of the tumor microenvironment (TME), including hypoxia, heterogeneity, and...

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Synthetically lethal nanoparticles for treatment of endometrial cancer

Cited by 59 publications

References 49 publications

Tunable Properties of Poly-DL-Lactide-Monomethoxypolyethylene Glycol Porous Microparticles for Sustained Release of Polyethylenimine-DNA Polyplexes

Tunable Properties of Poly-DL-Lactide-Monomethoxypolyethylene Glycol Porous Microparticles for Sustained Release of Polyethylenimine-DNA Polyplexes

MTDH/AEG-1 downregulation using pristimerin-loaded nanoparticles inhibits Fanconi anemia proteins and increases sensitivity to platinum-based chemotherapy

Precise Subcellular Organelle Targeting for Boosting Endogenous‐Stimuli‐Mediated Tumor Therapy

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