Modified antimetabolites-loaded lipid nanocapsules to enhance antitumor immunity

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Modified antimetabolitesloaded lipid nanocapsules to enhance antitumor immunity

Giovanna Lollo^1,2,3, Martina Bocchiardo^2,3, Kevin Matha^2,3, Marion Pitorre^2,3, Guillaume Bastiat^2,3, Jerome Bejaud^2,3, Maria Stella Sasso⁴, Susanna Mandruzzato^4,5, Vincenzo Bronte⁶, Ilaria Marigo⁵ and JeanPierre Benoit^2,3, (1)Faculty of PharmacyCNRS, LAGEP UMR 5007, University Claude Bernard Lyon 1, Lyon, FRANCE, (2)INSERM U 1066/CNRS 6021, Micro et nanomédecines translationnelles, Angers, FRANCE, (3)Université Angers, Faculty of Health, Pharmacy department, Angers, FRANCE, (4)Oncology and Immunology Sec, Dpt of Surgery, Oncology and Gastr, University of Padova, Padova, ITALY, (5)Istituto Oncologico Veneto, IOVIRCCS, Padova, ITALY, (6)Department of Medicine, Verona University Hospital, Verona, ITALY

Abstract Text:

Introduction: Myeloidderived suppressor cells (MDSCs) are critical players of tumorinduced

immunosuppression in mouse models and cancer patients. They accumulate in the spleen and cancers of tumorbearing hosts where they suppress Tcell activation, proliferation and cytotoxic function [1]. Previous studies demonstrated that some anticancer agents, in addition to their cytotoxic effects on tumor cells, were able to affect MDSCs. This occurs for antimetabolites like 5fluorouracile (5FU) and Gemcitabine (Gem) [2]. In this work, the potential activity of novel lipophilic 5FU and Gem derivatives encapsulated into lipid

nanocapsules (LNCs) to target monocytic (M)MDSC subset and tumor cells (pancreatic B6KPC3) was assessed. The aim was to study the immunogenic and anticancer properties of innovative nanosystems.

Methods: Gem and 5FU were modified to obtain monolauroylderivatives (GemC12 and 5FUC12). The derivatives were purified by chromatography on silica column and characterized by nuclear magnetic resonance. Blank and loadedLNCs were prepared using the phase inversion process [3]. Physicochemical characterization (size, dispersity, zeta potential and encapsulation efficiency) was performed. To study the in vitro induction of MMDSCs, the immunosuppressive activity and internalization assays of GemC12loaded LNCs, mouse bone marrow cells cultured in presence of GMCSF and IL6 were used. To investigate the efficacy of 5FUC12loaded LNCs, B6KPC3 cells were employed. Finally, as a preliminary in vivo study, the biodistribution of fluorescentloaded LNCs (i.v. or s.c.) using tumorbearing mice (EG7OVA subcutaneous model) was evaluated.

Results: Lipophilic derivatives, 5FUC12 and GemC12, were synthetized. The yield of the products recovered was 60% and 40% for 5FUC12 and GemC12, respectively. Blank, 5FUC12 and GemC12loaded LNCs showed an average size of 60 nm, dispersity index below 0.1 and neutral surface charge. The encapsulation efficiency of drugs was close to 100%. In vitro and in vivo studies highlighted that GemC12loaded LNCs were internalized and depleted selectively MMDSCs. Using K6PC3, we demonstrated that 5FUC12loaded LNCs exerted a toxic effect comparable to the commercial 5FUsolution. In vivo studies following i.v. or s.c.

administration of fluorescentloaded LNCs showed that LNCs reached peripheral tissues. As compared with i.v., following s.c. injection, fluorescent signal increased with time in the spleen, suggesting a slow LNCs absorption.

Conclusions: In the present study, lipophilic 5FUC12 and GemC12loaded LNC were obtained. GemC12

loaded LNCs were able to target MMDSCs in vivo and in vitro. Besides, 5FUC12loaded LNCs showed efficacy as anticancer drug in a pancreatic cell line. Further in vitro and in vivo therapeutic evaluations would disclose the full potential of these novel LNCs.

References:

1Bronte V Nat Commun. 2016, 12150.

2Apetoh L. et al. Curr Mol Med. 2011, 36572.

3Sasso MS et al. Biomaterials. 2016, 4762.

Presentation Primary Area Selection:

Overcoming Biological Barriers in Drug Delivery

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First Presenting Author Presenting Author Giovanna Lollo

Faculty of PharmacyCNRS, LAGEP UMR 5007, University Claude Bernard Lyon 1 Lyon,

FRANCE

INSERM U 1066/CNRS 6021, Micro et nanomédecines translationnelles Angers,

FRANCE

Université Angers, Faculty of Health, Pharmacy department Angers,

FRANCE

Email: giovanna.lollo@univlyon1.fr Will not be published

* Membership Number 142574 Is author a student or postdoc? No Second Author

Martina Bocchiardo

FRANCE

Email: martina.bocchiardo@edu.unito.it Will not be published

* Membership Number 142596 Is author a student or postdoc? Yes Third Author

Kevin Matha

FRANCE

Email: kevin.matha@etud.univangers.fr Will not be published

* Membership Number 142575 Is author a student or postdoc? Yes Fourth Author

Marion Pitorre

FRANCE

Presentation Secondary Area Selection:

Delivery of Complex and Labile Molecules Title:

Modified antimetabolitesloaded lipid nanocapsules to enhance antitumor immunity Submitter's Email Address:

giovanna.lollo@univlyon1.fr Learning Objectives:

1Design lipid nanocapsules loaded with novel lipophilic compounds.2Assess the activity of modified gemcitabinelipidic nanocapsules on MMDSCs and modified 5Fluorouracile on a pancreatic cell line (B6KPC3).3Define the role of nanoparticulate drug formulations in cancer immunotherapy.

Previously Published:

Abstract has not been previously submitted for consideration in other competitions or meetings.

Terms and Conditions:

I agree

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FRANCE

Email: marion.pitorre@univangers.fr Will not be published

* Membership Number 142576 Is author a student or postdoc? Yes Fifth Author

Guillaume Bastiat

FRANCE

Email: guillaume.bastiat@univangers.fr Will not be published

* Membership Number 133344 Is author a student or postdoc? No Sixth Author

Jerome Bejaud

FRANCE

Email: jerome.bejaud@univangers.fr Will not be published

* Membership Number 142577 Is author a student or postdoc? No Seventh Author

Maria Stella Sasso

Oncology and Immunology Sec, Dpt of Surgery, Oncology and Gastr, University of Padova Padova,

ITALY

Email: maristella.sasso@gmail.com Will not be published Is author a student or postdoc? No

Eighth Author

Susanna Mandruzzato

Oncology and Immunology Sec, Dpt of Surgery, Oncology and Gastr, University of Padova Padova,

ITALY

Istituto Oncologico Veneto, IOVIRCCS Padova,

ITALY

Email: susanna.mandruzzato@unipd.it Will not be published Is author a student or postdoc? No

Ninth Author Vincenzo Bronte

Department of Medicine, Verona University Hospital Verona,

ITALY

Email: vincenzo.bronte@univr.it Will not be published

* Membership Number 142578 Is author a student or postdoc? No Tenth Author

Ilaria Marigo

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Ilaria Marigo

Istituto Oncologico Veneto, IOVIRCCS Padova,

ITALY

Email: ilaria.marigo@ioveneto.it Will not be published

* Membership Number 142579 Is author a student or postdoc? No Eleventh Author

JeanPierre Benoit

FRANCE

Email: jeanpierre.benoit@univangers.fr Will not be published

* Membership Number 103403 Is author a student or postdoc? No

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