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Bifunctional Therapeutic Peptide Assembled Nanoparticles Exerting Improved Activities of Tumor Vessel Normalization and Immune Checkpoint Inhibition

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Advanced Healthcare Materials
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Mohammad Taleb
Mohammad Taleb
Mohammad Taleb
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Mona Atabakhshi Kashi at Coriolis Pharma
Mona Atabakhshi Kashi
Yazhou Wang
Yazhou Wang
Yazhou Wang
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Hamideh Rezvani Alanagh
Hamideh Rezvani Alanagh
Hamideh Rezvani Alanagh
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Abstract and Figures

The effectiveness of cancer immunotherapy is impaired by the dysfunctional vasculature of tumors. Created hypoxia zones and limited delivery of cytotoxic immune cells help to have immune resistance in tumor tissue. Structural and functional normalization of abnormal tumor vasculature provide vessels for more perfusion efficiency and drug delivery that result in alleviating the hypoxia in the tumor site and increasing infiltration of antitumor T cells. Taking advantage of peptide amphiphiles, herein, a novel peptide amphiphile nanoparticle composed of an antiangiogenic peptide (FSEC) and an immune checkpoint blocking peptide (DPPA) is designed and characterized. FSEC peptide is known to be involved in vessel normalization of tumors in vivo. DPPA is an inhibitory peptide of the PD‐1/PD‐L1 immune checkpoint pathway. The peptide amphiphile nanoparticle sets out to test whether simultaneous modulation of tumor vasculature and immune systems in the tumor microenvironment has a synergistic effect on tumor suppression. Increased intratumoral infiltration of immune cells following vascular normalization, and simultaneously blocking the immune checkpoint function of PD‐L1 reactivates effective immune responses to the tumors. In summary, the current study provides a new perspective on the regulation of tumor vessel normalization and immunotherapy based on functional peptide nanoparticles as nanomedicine for improved therapeutic purposes.
Characterization of DPPA and FD nanoparticles. a) TEM images of DPPA and FD nanoparticles before and after incubation with the legumain enzyme; scale bar = 100 nm. b,c) Corresponding size distribution and zeta potential of nanoformulations detected by DLS. Data are shown as the mean ± SD (n = 3). d) Enzyme responsiveness of FD peptide was monitored using MALDI‐TOF mass spectrometry.
Characterization of DPPA and FD nanoparticles. a) TEM images of DPPA and FD nanoparticles before and after incubation with the legumain enzyme; scale bar = 100 nm. b,c) Corresponding size distribution and zeta potential of nanoformulations detected by DLS. Data are shown as the mean ± SD (n = 3). d) Enzyme responsiveness of FD peptide was monitored using MALDI‐TOF mass spectrometry.
… 
In vitro functional characterization of FD and DPPA nanoparticles and other formulations. a) Cell viability of 4T1 cells and HUVECs that were treated with DPPA nanoparticles, FD nanoparticles, DPPA peptide, and FSEC peptide for 24 and 48 h (n = 3). b,c) Analyzing the antiangiogenic function of FD nanoparticles by transwell cell migration assay. Percentage of migrated HUVECs in a transwell assay after 8 h of incubation with the legumain enzyme indicated effects of FSEC peptide sequence after cleavage from FD nanoparticles. (Scale bar = 40 µm.) d,e) Capillary tube formation of HUVECs after incubation with FD nanoparticles in the absence and presence of the legumain enzyme. Percentages of inhibition were quantified using image analysis software. f) The binding efficiency of DPPA toward PD‐L1 was evaluated by flow cytometry. PE‐labeled anti‐PD‐L1 antibody was incubated with 4T1 cells in the presence or absence of DPPA peptide sequence.
In vitro functional characterization of FD and DPPA nanoparticles and other formulations. a) Cell viability of 4T1 cells and HUVECs that were treated with DPPA nanoparticles, FD nanoparticles, DPPA peptide, and FSEC peptide for 24 and 48 h (n = 3). b,c) Analyzing the antiangiogenic function of FD nanoparticles by transwell cell migration assay. Percentage of migrated HUVECs in a transwell assay after 8 h of incubation with the legumain enzyme indicated effects of FSEC peptide sequence after cleavage from FD nanoparticles. (Scale bar = 40 µm.) d,e) Capillary tube formation of HUVECs after incubation with FD nanoparticles in the absence and presence of the legumain enzyme. Percentages of inhibition were quantified using image analysis software. f) The binding efficiency of DPPA toward PD‐L1 was evaluated by flow cytometry. PE‐labeled anti‐PD‐L1 antibody was incubated with 4T1 cells in the presence or absence of DPPA peptide sequence.
… 
In vivo evaluation of designed sequences effect on the normalization of tumor vessel structures, leakiness, and hypoxia. a) FSEC peptide sequence act as a specific VEGF receptor antagonist and promotes vessel normalization through inhibition of angiogenesis. Double immunofluorescence staining of pericytes (anti‐αSMA antibody, green) and endothelial cells (anti‐CD31 antibody, red) visualized the regained vascular organizations in groups that have been treated by FSEC peptide sequence and in particular by FD nanoparticles. b) Vascular maturity was calculated through the ratio of pericytes coverage to endothelial cells. c) Changes in vascular leakage were evaluated by FITC–dextran in vivo 14 days after treatment with peptide sequences. Scale bars = 100 µm. d) Relative vessel leakiness. e) The modified Miles assay was used to assess vascular permeability in the tumor. Evans blue dye concentration shows significantly decreased vessel leakiness after the treatment of mice using FD nanoparticles. f) Confocal microscopy images of vessels perfused with FITC–lectin. Perfusion of vessels after normalization was increased meaningfully in FD nanoparticle treated group. Treatment with other sequences cannot normalize vessels, which represent dilation and leaked structure similar to untreated tumors. Scale bar = 100 µm. g) Relative vessel perfusion intensity. h) Immunohistochemical staining for HIF1α in tumor tissues of treatment groups. Hypoxic areas significantly decreased in groups treated by the FSEC peptide sequence or FD nanoparticles compared to other control groups. i) Decreased expression levels of HIF1α in the tumors after treatment by FSEC peptide sequences and FD nanoparticles indicate better tissue oxygenation and less hypoxic effect as a consequence of vessel normalization. Scale bar = 50 µm. The experiments were repeated three times.
In vivo evaluation of designed sequences effect on the normalization of tumor vessel structures, leakiness, and hypoxia. a) FSEC peptide sequence act as a specific VEGF receptor antagonist and promotes vessel normalization through inhibition of angiogenesis. Double immunofluorescence staining of pericytes (anti‐αSMA antibody, green) and endothelial cells (anti‐CD31 antibody, red) visualized the regained vascular organizations in groups that have been treated by FSEC peptide sequence and in particular by FD nanoparticles. b) Vascular maturity was calculated through the ratio of pericytes coverage to endothelial cells. c) Changes in vascular leakage were evaluated by FITC–dextran in vivo 14 days after treatment with peptide sequences. Scale bars = 100 µm. d) Relative vessel leakiness. e) The modified Miles assay was used to assess vascular permeability in the tumor. Evans blue dye concentration shows significantly decreased vessel leakiness after the treatment of mice using FD nanoparticles. f) Confocal microscopy images of vessels perfused with FITC–lectin. Perfusion of vessels after normalization was increased meaningfully in FD nanoparticle treated group. Treatment with other sequences cannot normalize vessels, which represent dilation and leaked structure similar to untreated tumors. Scale bar = 100 µm. g) Relative vessel perfusion intensity. h) Immunohistochemical staining for HIF1α in tumor tissues of treatment groups. Hypoxic areas significantly decreased in groups treated by the FSEC peptide sequence or FD nanoparticles compared to other control groups. i) Decreased expression levels of HIF1α in the tumors after treatment by FSEC peptide sequences and FD nanoparticles indicate better tissue oxygenation and less hypoxic effect as a consequence of vessel normalization. Scale bar = 50 µm. The experiments were repeated three times.
… 
In vivo immunomodulatory effects of nanoformulations. a) Immunohistochemistry images of CD8⁺ T cells infiltration into the tumors (red arrows) treated with peptide nanoparticles. b,c) Quantification of NK cells and CD8⁺ T cells in tumor tissues using flow cytometry. High infiltration of these cells after treatment by FD nanoparticles indicated the effectiveness of combined vascular normalization and immunotherapy. d,e) Concentrations of IFN‐γ and interleukin‐2 (IL‐2) were detected by an ELISA kit.
In vivo immunomodulatory effects of nanoformulations. a) Immunohistochemistry images of CD8⁺ T cells infiltration into the tumors (red arrows) treated with peptide nanoparticles. b,c) Quantification of NK cells and CD8⁺ T cells in tumor tissues using flow cytometry. High infiltration of these cells after treatment by FD nanoparticles indicated the effectiveness of combined vascular normalization and immunotherapy. d,e) Concentrations of IFN‐γ and interleukin‐2 (IL‐2) were detected by an ELISA kit.
… 
Tumor accumulation and biodistribution of peptide nanoparticles. a) In vivo evidence of tumor accumulation of FD nanoparticles 8 and 24 h after tail injection. b) Ex vivo fluorescence imaging of free Cy5.5 and Cy5.5‐labeled FD nanoparticles biodistribution in heart, liver, spleen, lung, kidney, and tumor 24 h postintravenous injection. c) Blood clearance and d) tumor growth curves of 4T1‐implanted tumors in BALB/c mice that were treated by FD nanoparticles alone or through the combinational chemotherapy with DOX. e) Picture of the dissected tumors of the mice 14 days after tumor inoculation.
+1
Tumor accumulation and biodistribution of peptide nanoparticles. a) In vivo evidence of tumor accumulation of FD nanoparticles 8 and 24 h after tail injection. b) Ex vivo fluorescence imaging of free Cy5.5 and Cy5.5‐labeled FD nanoparticles biodistribution in heart, liver, spleen, lung, kidney, and tumor 24 h postintravenous injection. c) Blood clearance and d) tumor growth curves of 4T1‐implanted tumors in BALB/c mice that were treated by FD nanoparticles alone or through the combinational chemotherapy with DOX. e) Picture of the dissected tumors of the mice 14 days after tumor inoculation.
… 
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RESEARCH ARTICLE
www.advhealthmat.de
Bifunctional Therapeutic Peptide Assembled Nanoparticles
Exerting Improved Activities of Tumor Vessel Normalization
and Immune Checkpoint Inhibition
Mohammad Taleb, Mona Atabakhshi-Kashi, Yazhou Wang, Hamideh Rezvani Alanagh,
Zeinab Farhadi Sabet, Fenfen Li, Keman Cheng, Chen Li, Yingqiu Qi, Guangjun Nie,*
and Zhao Ying*
The effectiveness of cancer immunotherapy is impaired by the dysfunctional
vasculature of tumors. Created hypoxia zones and limited delivery of cytotoxic
immune cells help to have immune resistance in tumor tissue. Structural and
functional normalization of abnormal tumor vasculature provide vessels for
more perfusion efficiency and drug delivery that result in alleviating the
hypoxia in the tumor site and increasing infiltration of antitumor T cells.
Taking advantage of peptide amphiphiles, herein, a novel peptide amphiphile
nanoparticle composed of an antiangiogenic peptide (FSEC) and an immune
checkpoint blocking peptide (DPPA) is designed and characterized. FSEC
peptide is known to be involved in vessel normalization of tumors in vivo.
DPPA is an inhibitory peptide of the PD-1/PD-L1 immune checkpoint pathway.
The peptide amphiphile nanoparticle sets out to test whether simultaneous
modulation of tumor vasculature and immune systems in the tumor
microenvironment has a synergistic effect on tumor suppression. Increased
intratumoral infiltration of immune cells following vascular normalization,
and simultaneously blocking the immune checkpoint function of PD-L1
reactivates effective immune responses to the tumors. In summary, the
current study provides a new perspective on the regulation of tumor vessel
normalization and immunotherapy based on functional peptide nanoparticles
as nanomedicine for improved therapeutic purposes.
1. Introduction
Immune-oncology therapies have emerged as an eective treat-
ment in cancer patients, engaging the immune system of
M. Taleb, Dr. M. Atabakhshi-Kashi, Dr. Y. Wang, Dr. H. Rezvani Alanagh,
Z.FarhadiSabet,F.Li,Dr.K.Cheng,C.Li,Prof.G.Nie,Prof.Z.Ying
CAS Key Laboratory for Biomedical Eects of Nanomaterials and
Nanosafety
CAS Center of Excellence in Nanoscience
National Center for Nanoscience and Technology
Beijing , P. R. China
E-mail: niegj@nanoctr.cn; zhaoying@nanoctr.cn
The ORCID identification number(s) for the author(s) of this article
can be found under https://doi.org/./adhm.
DOI: 10.1002/adhm.202100051
themselves to recognize and eradicate tu-
mor cells.[] In this regard, targeting in-
hibitory receptors on cytotoxic T cells
and/or tumor cells can constructively rein-
vigorate antitumor immune responses in
the tumor microenvironment (TME) and
partially modulate the immunosuppres-
sive microenvironment of tumors.[, ] Pro-
grammed cell death ligand- (PD-L) is
known as one of these inhibitory recep-
tors on cancerous cells which engages in
the PD-/PD-L axis and subsequently pre-
vents the killing capacity of T cells.[] In-
terference with the PD-/PD-L interac-
tion using immune checkpoint inhibitors
(ICIs) such as monoclonal antibodies or
specific peptide sequences have an eec-
tive impact on the enhancement of antitu-
mor immune responses. Rather than con-
ventional treatment methods in particular
cytotoxic chemotherapy and radiation ther-
apy, immune-mediated tumor therapy by
ICIs increase survival advantage and pro-
vide more durable clinical outcomes.[, ]
However, most of the patients do not drive
long-term benefits from ICIs monother-
apy because of acquired resistance that is
established by tumor-associated factors.[]
According to the clinical trials, inadequate intratumoral infiltra-
tion of immune cells and the diminished oxygen availability (hy-
poxia) in TME that raised from abnormal tumor vasculatures are
concomitant with ineective responses to ICIs.[, ]
M. Taleb, Dr. H. Rezvani Alanagh, Z. Farhadi Sabet, C. Li, Prof. G. Nie,
Prof. Z. Ying
Center of Materials Science and Optoelectronics Engineering
University of Chinese Academy of Sciences
Beijing , P. R. China
Dr.Y.Qi
School of Basic Medical Science
Zhengzhou University
Henan , China
Prof. G. Nie, Prof. Z. Ying
GBA Research Innovation Institute for Nanotechnology
Guangdong , P. R. China
Adv. Healthcare Mater. 2021,10,  ©  Wiley-VCH GmbH
2100051 (1 of 13)

Supplementary resources (2)

adhm202100051-sup-0001-suppmat.pdf
Data
June 2021
Mohammad Taleb · Mona Atabakhshi Kashi · Yazhou Wang · Hamideh Rezvani Alanagh · Zhao Ying
adhm202100051-sup-0001-suppmat (1).pdf
Data
May 2021
Mohammad Taleb · Mona Atabakhshi Kashi · Yazhou Wang · Hamideh Rezvani Alanagh · Zhao Ying
... The fundamental reason for the low accumulation of drugs within the tumor is the insufficient blood perfusion within the tumor interior [11]. Studies have revealed that the local capillary venous pressure within tumors is approximately 20 mm Hg, while the interstitial pressure ranges from 20 to 130 mm Hg [12]. ...
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  • Jan 2020
  • J AM CHEM SOC
The limited efficacy of single-agent immune checkpoint inhibitors in treating tumors has prompted investigations on their combination partners. Here, a tumor-homing indoleamine 2, 3-dioxygenase (IDO) nanoinhibitor is reported to selectively inhibit immunosuppressive IDO pathway in the tumor microenvironment. It is self-assembled from a modularly designed peptide-drug conjugate containing a hydrophilic targeting motif (arginyl-glycyl-aspartic acid; RGD), two protonatable histi-dines and an ester bond-linked hydrophobic IDO inhibitor, which exhibits pH-responsive disassembly and esterase-catalyzed drug release. Markedly, it achieved potent and persistent inhibition of intratumoral IDO activity with reduced systemic toxicity, which greatly enhanced the therapeutic efficacy of programmed cell death-ligand 1 blockade in vivo. Overall, this study provides a promising paradigm of combinatorial normalization immunotherapy by exploiting a targeted IDO nanoinhibitor to augment the anti-tumor immunity of checkpoint inhibitors.
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Modulating the tumor microenvironment with new therapeutic nanoparticles: A promising paradigm for tumor treatment
Article
  • Nov 2019
To better make nanomedicine entering the clinic, developing new rationally designed nanotherapeutics with a deeper understanding of tumor biology is required. The tumor microenvironment is similar to the inflammatory response in a healing wound, the milieu of which promotes tumor cell invasion and metastasis. Successful targeting of the microenvironmental components with effective nanotherapeutics to modulate the tumor microvessels or restore the homeostatic mechanisms in the tumor stroma will offer new hope for cancer treatment. We here highlight the progress in constructing nanotherapeutics to target or modulate the tumor microenvironment. We discuss the factors necessary for nanomedicines to become a new paradigm in cancer therapy, including the selection of drugs and therapeutic targets, controllable synthesis, and tempo‐spatial drug release.
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