Biodegradable Reduce Expenditure Bioreactor For Augmented Sonodynamic Therapy Via Regulating Tumor Hypoxia And Inducing Pro-Death Autophagy

Abstract Backgrounds: Sonodynamic therapy (SDT) as an emerging reactive oxygen species (ROS)-mediated antitumor means is still hampered by the rapid depletion of oxygen, as well as hypoxic tumor microenvironment. Instead of the currently coping strategies through amplifying endogenous O2 level, herein, a biodegradable O2 economizer is described as a reduce expenditure bioreactor for augmenting SDT efficacy. Results: We have successfully fabricated the O2 economizer (HMME@HMONs-3BP-PEG, HHBP) by the conjugation of respiration inhibitor 3-bromopyruvate (3BP) with hollow mesoporous organosilica nanoparticles (HMONs), followed by the loading of organic sonosensitizers (HMME) and further surface modification of poly(ethylene glycol) (PEG). The engineered HHBP features controllable pH/GSH/US-sensitive drug release. The exposed 3BP could effectively inhibit cell respiration for restraining the oxygen consumption, which could alleviate the tumor hypoxia. More interestingly, it could exorbitantly elevate the autophagy level, which in turn induce excessive activation of autophagy for promoting the therapeutic efficacy. As a result, accompanied with suppressing O2-consumption and triggering pro-death autophagy strategy, the HHBP achieves remarkable antitumor activity, which has been systematically validated both in vivo and in vitro assays. Conclusion: This work not only provides a reduce expenditure strategy for enduring SDT, but also represents an inquisitive strategy for tumor treatments via inducing pro-death autophagy.

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Biodegradable reduce expenditure bioreactor for augmented sonodynamic therapy via regulating tumor hypoxia and inducing pro-death autophagy

Journal of Nanobiotechnology ◽

10.1186/s12951-021-01166-y ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Weijuan Zou ◽

Junnian Hao ◽

Jianrong Wu ◽

Xiaojun Cai ◽

Bing Hu ◽

...

Keyword(s):

Tumor Hypoxia ◽

Monomethyl Ether ◽

In Vitro Assays ◽

Sonodynamic Therapy ◽

Mesoporous Organosilica ◽

Hypoxic Tumor ◽

Poly Ethylene ◽

Excessive Activation

Abstract Backgrounds Sonodynamic therapy (SDT) as an emerging reactive oxygen species (ROS)-mediated antitumor strategy is challenged by the rapid depletion of oxygen, as well as the hypoxic tumor microenvironment. Instead of the presently available coping strategies that amplify the endogenous O2 level, we have proposed a biodegradable O2 economizer to reduce expenditure for augmenting SDT efficacy in the present study. Results We successfully fabricated the O2 economizer (HMME@HMONs-3BP-PEG, HHBP) via conjugation of respiration inhibitor 3-bromopyruvate (3BP) with hollow mesoporous organosilica nanoparticles (HMONs), followed by the loading of organic sonosensitizers (hematoporphyrin monomethyl ether; HMME) and further surface modification of poly(ethylene glycol) (PEG). The engineered HHBP features controllable pH/GSH/US-sensitive drug release. The exposed 3BP could effectively inhibit cell respiration for restraining the oxygen consumption, which could alleviate the tumor hypoxia conditions. More interestingly, it could exorbitantly elevate the autophagy level, which in turn induced excessive activation of autophagy for promoting the therapeutic efficacy. As a result, when accompanied with suppressing O2-consumption and triggering pro-death autophagy strategy, the HHBP could achieve the remarkable antitumor activity, which was systematically validated both in vivo and in vitro assays. Conclusions This work not only provides a reduce expenditure means for enduring SDT, but also represents an inquisitive strategy for tumor treatments by inducing pro-death autophagy. Graphical Abstract

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Local Toxicity of Topically Administrated Thermoresponsive Systems: In Vitro Studies with In Vivo Correlation

Toxicologic Pathology ◽

10.1177/0192623318810199 ◽

2018 ◽

Vol 47 (3) ◽

pp. 426-432 ◽

Cited By ~ 3

Author(s):

Sivan Yogev ◽

Ayelet Shabtay-Orbach ◽

Abraham Nyska ◽

Boaz Mizrahi

Keyword(s):

Block Copolymer ◽

Ethylene Glycol ◽

Medical Devices ◽

Poly Lactic Acid ◽

Poly Ethylene Glycol ◽

Thermoresponsive Polymers ◽

Wide Range ◽

Poly Ethylene

Thermoresponsive materials have the ability to respond to a small change in temperature—a property that makes them useful in a wide range of applications and medical devices. Although very promising, there is only little conclusive data about the cytotoxicity and tissue toxicity of these materials. This work studied the biocompatibility of three Food and Drug Administration approved thermoresponsive polymers: poly( N-isopropyl acrylamide), poly(ethylene glycol)-poly(propylene glycol)-poly(ethylene glycol) tri-block copolymer, and poly(lactic acid-co-glycolic acid) and poly(ethylene glycol) tri-block copolymer. Fibroblast NIH 3T3 and HaCaT keratinocyte cells were used for the cytotoxicity testing and a mouse model for the in vivo evaluation. In vivo results generally showed similar trends as the results seen in vitro, with all tested materials presenting a satisfactory biocompatibility in vivo. pNIPAM, however, showed the highest toxicity both in vitro and in vivo, which was explained by the release of harmful monomers and impurities. More data focusing on the biocompatibility of novel thermoresponsive biomaterials will facilitate the use of existing and future medical devices.

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In vivo and in vitro degradation of poly(ether ester) block copolymers based on poly(ethylene glycol) and poly(butylene terephthalate)

Biomaterials ◽

10.1016/s0142-9612(03)00495-2 ◽

2004 ◽

Vol 25 (2) ◽

pp. 247-258 ◽

Cited By ~ 59

Author(s):

A.A. Deschamps ◽

A.A. van Apeldoorn ◽

H. Hayen ◽

J.D. de Bruijn ◽

U. Karst ◽

...

Keyword(s):

Block Copolymers ◽

Ethylene Glycol ◽

Poly Ethylene Glycol ◽

In Vitro Degradation ◽

Butylene Terephthalate ◽

Poly Ethylene ◽

Ether Ester

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A pH and Redox Dual Responsive 4-Arm Poly(ethylene glycol)-block-poly(disulfide histamine) Copolymer for Non-Viral Gene Transfection in Vitro and in Vivo

International Journal of Molecular Sciences ◽

10.3390/ijms15059067 ◽

2014 ◽

Vol 15 (5) ◽

pp. 9067-9081 ◽

Cited By ~ 13

Author(s):

Kangkang An ◽

Peng Zhao ◽

Chao Lin ◽

Hongwei Liu

Keyword(s):

Ethylene Glycol ◽

Gene Transfection ◽

Viral Gene ◽

Poly Ethylene Glycol ◽

Dual Responsive ◽

Poly Ethylene

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In vitro and in vivo study of poly(ethylene glycol) conjugated ketoprofen to extend the duration of action

International Journal of Pharmaceutics ◽

10.1016/j.ijpharm.2007.03.045 ◽

2007 ◽

Vol 341 (1-2) ◽

pp. 50-57 ◽

Cited By ~ 9

Author(s):

Hoo-Kyun Choi ◽

Myung-Kwan Chun ◽

Se Hee Lee ◽

Mee Hee Jang ◽

Hee Doo Kim ◽

...

Keyword(s):

Ethylene Glycol ◽

In Vivo Study ◽

Poly Ethylene Glycol ◽

Duration Of Action ◽

Poly Ethylene

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Atovaquone-HSA nano-drugs enhance the efficacy of PD-1 blockade immunotherapy by alleviating hypoxic tumor microenvironment

Journal of Nanobiotechnology ◽

10.1186/s12951-021-01034-9 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Simeng Wang ◽

Xinrui Zhou ◽

Zekun Zeng ◽

Mengjun Sui ◽

Lihong Chen ◽

...

Keyword(s):

Tumor Microenvironment ◽

Disulfide Bonds ◽

Tumor Targeting ◽

Tumor Hypoxia ◽

Animal Experiments ◽

Complex Iii ◽

Mitochondrial Activity ◽

Hypoxic Tumor

Abstract Background Hypoxia is inherent character of most solid malignancies, leading to the failure of chemotherapy, radiotherapy and immunotherapy. Atovaquone, an anti-malaria drug, can alleviate tumor hypoxia by inhibiting mitochondrial complex III activity. The present study exploits atovaquone/albumin nanoparticles to improve bioavailability and tumor targeting of atovaquone, enhancing the efficacy of anti-PD-1 therapy by normalizing tumor hypoxia. Methods We prepared atovaquone-loaded human serum albumin (HSA) nanoparticles stabilized by intramolecular disulfide bonds, termed HSA-ATO NPs. The average size and zeta potential of HSA-ATO NPs were measured by particle size analyzer. The morphology of HSA-ATO NPs was characterized by transmission electron microscope (TEM). The bioavailability and safety of HSA-ATO NPs were assessed by animal experiments. Flow cytometry and ELISA assays were used to evaluate tumor immune microenvironment. Results Our data first verified that atovaquone effectively alleviated tumor hypoxia by inhibiting mitochondrial activity both in vitro and in vivo, and successfully encapsulated atovaquone in vesicle with albumin, forming HSA-ATO NPs of approximately 164 nm in diameter. We then demonstrated that the HSA-ATO NPs possessed excellent bioavailability, tumor targeting and a highly favorable biosafety profile. When combined with anti-PD-1 antibody, we observed that HSA-ATO NPs strongly enhanced the response of mice bearing tumor xenografts to immunotherapy. Mechanistically, HSA-ATO NPs promoted intratumoral CD8+ T cell recruitment by alleviating tumor hypoxia microenvironment, thereby enhancing the efficacy of anti-PD-1 immunotherapy. Conclusions Our data provide strong evidences showing that HSA-ATO NPs can serve as safe and effective nano-drugs to enhance cancer immunotherapy by alleviating hypoxic tumor microenvironment. Graphic abstract

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