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Research Article
Peng Hou
Xi'an Jiaotong University Medical College First Affiliated Hospital
Corresponding Author
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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. Immunofluorescence 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 improving tumor hypoxia microenvironment, thereby enhancing the efficacy of anti-PD-1 immunotherapy.
Conclusion: Our data provide strong evidences showing that HSA-ATO NPs can serve as safe and effective nano-drugs to enhance cancer immunotherapy by improving hypoxic tumor microenvironment.
Keywords
Hypoxic tumor microenvironment, Atovaquone, Anti-PD-1 therapy, Nano-drugs, Tumor targeting
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CURRENT STATUS: Under Review
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Posted 17 May, 2021
No community comments so far
Editorial decision: Major revision
On 28 May, 2021
Review #2 received
Received 24 May, 2021
Review #1 received
Received 17 May, 2021
Reviewer #2 agreed
On 12 May, 2021
Reviews received
Received 12 May, 2021
Reviewers invited
Invitations sent on 12 May, 2021
Reviewer #1 agreed
On 11 May, 2021
Editor assigned
On 09 May, 2021
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On 09 May, 2021
Editor invited
On 09 May, 2021
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This preprint is under consideration at Journal of Nanobiotechnology. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research Article
Peng Hou
Xi'an Jiaotong University Medical College First Affiliated Hospital
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 1
Posted 17 May, 2021
No community comments so far
Editorial decision: Major revision
On 28 May, 2021
Review #2 received
Received 24 May, 2021
Review #1 received
Received 17 May, 2021
Reviewer #2 agreed
On 12 May, 2021
Reviews received
Received 12 May, 2021
Reviewers invited
Invitations sent on 12 May, 2021
Reviewer #1 agreed
On 11 May, 2021
Editor assigned
On 09 May, 2021
Submission checks complete
On 09 May, 2021
Editor invited
On 09 May, 2021
First submitted
On 06 May, 2021
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
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. Immunofluorescence 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 improving tumor hypoxia microenvironment, thereby enhancing the efficacy of anti-PD-1 immunotherapy.
Conclusion: Our data provide strong evidences showing that HSA-ATO NPs can serve as safe and effective nano-drugs to enhance cancer immunotherapy by improving hypoxic tumor microenvironment.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
This is a list of supplementary files associated with this preprint. Click to download.
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