Co-delivery of RNAi and chemokine by polyarginine nanocapsules enables the modulation of myeloid-derived suppressor cells

A.M. Ledo, M.S. Sasso, V. Bronte, I. Marigo, B.J. Boyd, M. Garcia-Fuentes, M.J. Alonso

Research output: Contribution to journalArticle

Abstract

Myeloid-Derived Suppressor Cells (MDSCs), immunosuppressive cells that promote tumor growth, represent an attractive target in cancer immunotherapy. However, the clinical success of this strategy is limited by the lack of efficient drug delivery vehicles targeting this cell compartment. The objective of this work was to develop a delivery carrier, multilayer polymer nanocapsules, with the capacity to co-encapsulate two types of immunomodulatory drugs, a chemokine and an RNAi sequence, aimed at reverting MDSC-mediated immunosuppression. The chemokine CCL2, intended to attract monocyte-macrophage MDSCs, was encapsulated within the L2 inverse micellar aqueous domains of the lipid core of these nanocapsules. On the other hand, two different RNAi sequences that modulate the CCAAT/enhancer-binding protein beta (C/EBPβ) pathway, shC/EBPβ and miR 142-3p, were successfully associated to their polymer shell. These RNAi sequences were covered by subsequent layers of polyarginine and hyaluronic acid, thereby creating multi-layered assemblies that protected them and facilitated their targeted delivery. The in vitro studies performed in primary MDSCs cultures showed the capacity of miR 142-3p-loaded nanocapsules to reduce the highly immunosuppressive monocyte-macrophage subset. Additionally, the encapsulation of CCL2 within the nanocapsules induced a potent monocyte-macrophage chemoattraction that could be used to direct the therapy to these cell subsets. Finally, in vitro and in vivo studies showed the capacity of shC/EBPβ-loaded nanocapsules to downregulate C/EBPβ levels in MDSCs and to reduce monocyte differentiation into tumor-associated macrophages in an MCA-203 fibrosarcoma mice model. In conclusion, the multilayer polymer nanocapsules described here are efficient vehicles for the co-delivery of proteins and RNA, and are potential candidates as nanomedicines for the modulation of MDSCs. © 2018 Elsevier B.V.
Original languageEnglish
Pages (from-to)60-73
Number of pages14
JournalJournal of Controlled Release
Volume295
DOIs
Publication statusPublished - Feb 10 2019

Fingerprint

Nanocapsules
RNA Interference
Chemokines
Monocytes
Macrophages
CCAAT-Enhancer-Binding Protein-beta
Polymers
Immunosuppressive Agents
Nanomedicine
Neoplasms
Chemokine CCL2
Fibrosarcoma
Hyaluronic Acid
Cell- and Tissue-Based Therapy
Pharmaceutical Preparations
Immunotherapy
Immunosuppression
polyarginine
Myeloid-Derived Suppressor Cells
Down-Regulation

Keywords

  • Body fluids
  • Chloroacetic acid
  • Controlled drug delivery
  • Cytology
  • Hyaluronic acid
  • Macrophages
  • Mammals
  • Modulation
  • Multilayers
  • Nanocapsules
  • Proteins
  • Tumors, Cancer immunotherapy
  • Ccaat/enhancer-binding proteins
  • CCL2
  • Efficient drug delivery
  • MDSCs
  • Polymer nanocapsules
  • RNAi
  • Tumor associated macrophages, Targeted drug delivery, CCAAT enhancer binding protein beta
  • chemokine
  • drug vehicle
  • hyaluronic acid
  • labrasol
  • lipid
  • monocyte chemotactic protein 1
  • nanocapsule
  • ovalbumin
  • polyarginine
  • polymer
  • RNA
  • short hairpin RNA, adoptive immunotherapy
  • adsorption
  • animal cell
  • animal experiment
  • animal model
  • Article
  • cancer immunotherapy
  • cell differentiation assay
  • cell migration assay
  • controlled release formulation
  • controlled study
  • fibrosarcoma
  • human
  • human cell
  • immunosuppressive treatment
  • in vitro study
  • macrophage
  • monocyte
  • morphology
  • mouse
  • myeloid-derived suppressor cell
  • nanotechnology
  • nonhuman
  • particle size
  • priority journal
  • reverse transcription polymerase chain reaction
  • RNA extraction
  • RNA interference
  • transmission electron microscopy
  • tumor associated leukocyte

Cite this

Co-delivery of RNAi and chemokine by polyarginine nanocapsules enables the modulation of myeloid-derived suppressor cells. / Ledo, A.M.; Sasso, M.S.; Bronte, V.; Marigo, I.; Boyd, B.J.; Garcia-Fuentes, M.; Alonso, M.J.

In: Journal of Controlled Release, Vol. 295, 10.02.2019, p. 60-73.

Research output: Contribution to journalArticle

Ledo, A.M. ; Sasso, M.S. ; Bronte, V. ; Marigo, I. ; Boyd, B.J. ; Garcia-Fuentes, M. ; Alonso, M.J. / Co-delivery of RNAi and chemokine by polyarginine nanocapsules enables the modulation of myeloid-derived suppressor cells. In: Journal of Controlled Release. 2019 ; Vol. 295. pp. 60-73.
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T1 - Co-delivery of RNAi and chemokine by polyarginine nanocapsules enables the modulation of myeloid-derived suppressor cells

AU - Ledo, A.M.

AU - Sasso, M.S.

AU - Bronte, V.

AU - Marigo, I.

AU - Boyd, B.J.

AU - Garcia-Fuentes, M.

AU - Alonso, M.J.

N1 - cited By 0

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N2 - Myeloid-Derived Suppressor Cells (MDSCs), immunosuppressive cells that promote tumor growth, represent an attractive target in cancer immunotherapy. However, the clinical success of this strategy is limited by the lack of efficient drug delivery vehicles targeting this cell compartment. The objective of this work was to develop a delivery carrier, multilayer polymer nanocapsules, with the capacity to co-encapsulate two types of immunomodulatory drugs, a chemokine and an RNAi sequence, aimed at reverting MDSC-mediated immunosuppression. The chemokine CCL2, intended to attract monocyte-macrophage MDSCs, was encapsulated within the L2 inverse micellar aqueous domains of the lipid core of these nanocapsules. On the other hand, two different RNAi sequences that modulate the CCAAT/enhancer-binding protein beta (C/EBPβ) pathway, shC/EBPβ and miR 142-3p, were successfully associated to their polymer shell. These RNAi sequences were covered by subsequent layers of polyarginine and hyaluronic acid, thereby creating multi-layered assemblies that protected them and facilitated their targeted delivery. The in vitro studies performed in primary MDSCs cultures showed the capacity of miR 142-3p-loaded nanocapsules to reduce the highly immunosuppressive monocyte-macrophage subset. Additionally, the encapsulation of CCL2 within the nanocapsules induced a potent monocyte-macrophage chemoattraction that could be used to direct the therapy to these cell subsets. Finally, in vitro and in vivo studies showed the capacity of shC/EBPβ-loaded nanocapsules to downregulate C/EBPβ levels in MDSCs and to reduce monocyte differentiation into tumor-associated macrophages in an MCA-203 fibrosarcoma mice model. In conclusion, the multilayer polymer nanocapsules described here are efficient vehicles for the co-delivery of proteins and RNA, and are potential candidates as nanomedicines for the modulation of MDSCs. © 2018 Elsevier B.V.

AB - Myeloid-Derived Suppressor Cells (MDSCs), immunosuppressive cells that promote tumor growth, represent an attractive target in cancer immunotherapy. However, the clinical success of this strategy is limited by the lack of efficient drug delivery vehicles targeting this cell compartment. The objective of this work was to develop a delivery carrier, multilayer polymer nanocapsules, with the capacity to co-encapsulate two types of immunomodulatory drugs, a chemokine and an RNAi sequence, aimed at reverting MDSC-mediated immunosuppression. The chemokine CCL2, intended to attract monocyte-macrophage MDSCs, was encapsulated within the L2 inverse micellar aqueous domains of the lipid core of these nanocapsules. On the other hand, two different RNAi sequences that modulate the CCAAT/enhancer-binding protein beta (C/EBPβ) pathway, shC/EBPβ and miR 142-3p, were successfully associated to their polymer shell. These RNAi sequences were covered by subsequent layers of polyarginine and hyaluronic acid, thereby creating multi-layered assemblies that protected them and facilitated their targeted delivery. The in vitro studies performed in primary MDSCs cultures showed the capacity of miR 142-3p-loaded nanocapsules to reduce the highly immunosuppressive monocyte-macrophage subset. Additionally, the encapsulation of CCL2 within the nanocapsules induced a potent monocyte-macrophage chemoattraction that could be used to direct the therapy to these cell subsets. Finally, in vitro and in vivo studies showed the capacity of shC/EBPβ-loaded nanocapsules to downregulate C/EBPβ levels in MDSCs and to reduce monocyte differentiation into tumor-associated macrophages in an MCA-203 fibrosarcoma mice model. In conclusion, the multilayer polymer nanocapsules described here are efficient vehicles for the co-delivery of proteins and RNA, and are potential candidates as nanomedicines for the modulation of MDSCs. © 2018 Elsevier B.V.

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KW - Cytology

KW - Hyaluronic acid

KW - Macrophages

KW - Mammals

KW - Modulation

KW - Multilayers

KW - Nanocapsules

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KW - Tumors, Cancer immunotherapy

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KW - labrasol

KW - lipid

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KW - ovalbumin

KW - polyarginine

KW - polymer

KW - RNA

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KW - adsorption

KW - animal cell

KW - animal experiment

KW - animal model

KW - Article

KW - cancer immunotherapy

KW - cell differentiation assay

KW - cell migration assay

KW - controlled release formulation

KW - controlled study

KW - fibrosarcoma

KW - human

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KW - in vitro study

KW - macrophage

KW - monocyte

KW - morphology

KW - mouse

KW - myeloid-derived suppressor cell

KW - nanotechnology

KW - nonhuman

KW - particle size

KW - priority journal

KW - reverse transcription polymerase chain reaction

KW - RNA extraction

KW - RNA interference

KW - transmission electron microscopy

KW - tumor associated leukocyte

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JO - Journal of Controlled Release

JF - Journal of Controlled Release

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