Bifunctional liposomes reduce the chemotherapy resistance of doxorubicin induced by reactive oxygen species

Xu, Lei; Zhang, Zhicheng; Ding, Yawen; Wang, Li; Cheng, Yali; Meng, Lingsen; Wu, Jinhui; Yuan, Ahu; Hu, Yiqiao; Zhu, Yishen

doi:10.1039/c9bm00590k

Cited by 29 publications

(16 citation statements)

References 30 publications

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“…The acidic environment causes ionization of weakly basic drugs like Dox and, therefore, lesser cellular uptake of ionized Dox. Another possibility for lesser Dox toxicity in hypoxia would be the suppression of ROS-mediated cytotoxicity of Dox in hypoxia, as already reported (Khan et al, 2019 ; Xu et al, 2019 ; He et al, 2020 ). These results were different from those we got after inhibition of CA-IX.…”

Section: Serum Stability Studiesmentioning

confidence: 68%

Co-delivery of carbonic anhydrase IX inhibitor and doxorubicin as a promising approach to address hypoxia-induced chemoresistance

Amin

Ali

et al. 2022

Drug Delivery

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Hypoxia, an oxygen-deprived condition of the tumor, is one of the major reasons for resistance to chemotherapy. Carbonic anhydrases are generally involved in pH homeostasis in normal conditions, but in solid tumors having a strong relation with hypoxia, the carbonic anhydrase IX (CA-IX) enzyme is overexpressed and results in an extracellular acidic environment. For most weakly basic anticancer drugs, including doxorubicin (Dox), the ionization in an acidic environment limits their cellular uptake, and consequently, the tumor exposure to the drug at sub-therapeutic concentration comes out as chemoresistance. Herein, a combined drug delivery system of liposomes and mesoporous silica nanoparticles (MSNPs) was developed for the co-delivery of the CA-IX enzyme inhibitor and Dox in hypoxic condition. The unique structure of MSNPs with higher surface area was utilized for higher drug loading and sustained release of Dox. Additionally, the biocompatible nature of liposomal coating as a second loading site for the CA-IX enzyme inhibitor has provided gatekeeping effects at pore opening to avoid premature drug release. Lipid coated MSNPs as a co-delivery system for Dox and the CA-IX inhibitor have synergistic cytotoxic effects against MDA-MB 231 breast cancer cells in hypoxic conditions. These findings assure the potential of this drug delivery system to overcome hypoxia-related chemoresistance.

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Section: Serum Stability Studiesmentioning

confidence: 68%

Co-delivery of carbonic anhydrase IX inhibitor and doxorubicin as a promising approach to address hypoxia-induced chemoresistance

Amin

Ali

et al. 2022

Drug Delivery

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“…After the whole treatment and euthanasia, the major organs and tumors were harvested for H&E staining. In addition, the HIF-1α expression in MCF-7 cells tumor-bearing mice after treatment as above was also analyzed by HIF-1α immunohistochemical staining assay. , Besides, to explore in vivo drug pharmacokinetics, free DOX and DOX@MCIP were injected into 4-week-old BALB/c female mice. At certain time intervals, serum was gathered and the DOX concentration was determined by HPLC …”

Section: Methodsmentioning

confidence: 99%

Oxygen-Abundant and pH/NIR Dual-Responsive Nanocarriers for Tumor Hypoxia Reduction Therapy

Zhuang

Zhang

Xuan

et al. 2021

ACS Appl. Nano Mater.

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Pre-existing tumor hypoxia and oxygen consumption by photodynamic therapy (PDT) always generate an inadequate oxygen supply, which often contributes to other therapy resistance, especially for aerobic treatments such as chemotherapy. In order to overcome this problem, we synthesized a chitosan (CS)-capped pH-/NIR-dual responsive and perfluorocarbon-based oxygen self-enriching photodynamic therapy nanosystem which could codeliver oxygen, photosensitizer, and chemotherapeutic drug. Simultaneously, in vitro results revealed that DOX release was stimulated by the acidic pH value with CS as a pH-responsive layer and rising temperature caused by the photothermal effect with an 808 nm laser, which could effectively reduce the nonspecific toxicity caused by premature drug release. Furthermore, due to the higher oxygen-carrying capability of perfluorocarbon, the decreased expression of the hypoxia-inducible factor-1α (HIF-1α) of tumors, as well as the significantly intense photodynamic effect and longer singlet ( 1 O 2 ) lifetime of the loaded photosensitizer, the elevated cytotoxicity was improved. More importantly, both in vitro and in vivo results showed that drug-loaded nanoparticles with oxygen-abundant properties achieved a similar anticancer therapy in both normoxic and hypoxic conditions against the difficulty led by deficient oxygen, as well as a good cellular internalization. Summarily, all these results pointed out that such a pH-/NIR-dual responsive drug carrier could enhance the synergetic anticancer therapy of chemotherapy and PDT by alleviation of tumor hypoxia, which provided a tempting controllable and multifunctional therapeutic application.

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“…Again, UPR-dependent and hypoxia-dependent axes synergize, because HIF-1α induces FOXO-1 transcription [171], promotes protective autophagy [172] and activates PERK/eIF2α/ATF4 axis [56]. By cooperating with HIF-1α in up-regulating MMP9 [173], PERK and HIF-1α also promote migration, helping cancer cells to leave unfavorable environments and escape from cytotoxic agents. As mentioned above, Nrf2 is also activated by PERK and confers chemoresistance by up-regulating MRP1 [99] and anti-oxidant enzymes [170].…”

Section: The Crosstalk Between Hypoxia and Upr-dependent Circuitries Induces Chemoresistancementioning

confidence: 99%

“…The disadvantage of these inhibitors is their aspecificity. In order to overcome this limitation, the first liposomal formulations containing acriflavine co-encapsulated with doxorubicin have been produced, and demostrated a superior tumor targeting and anti-tumor efficacy than doxorubicin alone [173]. Currently, more than 100 trials are testing HIF-1α inhibitors as anti-cancer agents (https://clinicaltrials.gov/ct2/results/ details?cond=Cancer&term=HIF), despite the results were below the expectations.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Hypoxia, endoplasmic reticulum stress and chemoresistance: dangerous liaisons

Akman

Belisario

Salaroglio

et al. 2021

J Exp Clin Cancer Res

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Solid tumors often grow in a micro-environment characterized by < 2% O2 tension. This condition, together with the aberrant activation of specific oncogenic patwhays, increases the amount and activity of the hypoxia-inducible factor-1α (HIF-1α), a transcription factor that controls up to 200 genes involved in neoangiogenesis, metabolic rewiring, invasion and drug resistance. Hypoxia also induces endoplasmic reticulum (ER) stress, a condition that triggers cell death, if cells are irreversibly damaged, or cell survival, if the stress is mild.Hypoxia and chronic ER stress both induce chemoresistance. In this review we discuss the multiple and interconnected circuitries that link hypoxic environment, chronic ER stress and chemoresistance. We suggest that hypoxia and ER stress train and select the cells more adapted to survive in unfavorable conditions, by activating pleiotropic mechanisms including apoptosis inhibition, metabolic rewiring, anti-oxidant defences, drugs efflux. This adaptative process unequivocally expands clones that acquire resistance to chemotherapy.We believe that pharmacological inhibitors of HIF-1α and modulators of ER stress, although characterized by low specificty and anti-cancer efficacy when used as single agents, may be repurposed as chemosensitizers against hypoxic and chemorefractory tumors in the next future.

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Bifunctional liposomes reduce the chemotherapy resistance of doxorubicin induced by reactive oxygen species

Abstract: A biofunctional liposome containing acriflavine (ACF) and doxorubicin (DOX) for reducing the chemotherapy resistance of DOX induced by reactive oxygen species.

Cited by 29 publications

References 30 publications

Co-delivery of carbonic anhydrase IX inhibitor and doxorubicin as a promising approach to address hypoxia-induced chemoresistance

Co-delivery of carbonic anhydrase IX inhibitor and doxorubicin as a promising approach to address hypoxia-induced chemoresistance

Oxygen-Abundant and pH/NIR Dual-Responsive Nanocarriers for Tumor Hypoxia Reduction Therapy

Hypoxia, endoplasmic reticulum stress and chemoresistance: dangerous liaisons

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