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Drug Delivery and Translational Research

, Volume 9, Issue 1, pp 260–272 | Cite as

Co-delivery of curcumin and doxorubicin in PEGylated liposomes favored the antineoplastic C26 murine colon carcinoma microenvironment

  • Alina Sesarman
  • Lucia Tefas
  • Bianca Sylvester
  • Emilia Licarete
  • Valentin Rauca
  • Lavinia Luput
  • Laura Patras
  • Sebastian Porav
  • Manuela BanciuEmail author
  • Alina Porfire
Original Article
  • 71 Downloads

Abstract

Our recent studies have demonstrated that the antitumor efficacy of doxorubicin (DOX), administered in long-circulating liposomes (LCL), could be considerably improved after its co-encapsulation with curcumin (CURC). Thus, the question addressed within this article is whether LCL-CURC-DOX can be exploited more efficiently than liposomal DOX for future colorectal cancer therapy. Therefore, we investigated the physicochemical and biological properties of LCL-CURC-DOX and the mechanisms of its antitumor activity in C26 murine colon carcinoma in vivo. Our results proved that the developed nanoformulation based on the co-encapsulation of CURC and DOX met the requirements of a modern drug delivery system for future cancer therapy, demonstrating enhanced antitumor activity on C26 colon carcinoma in vivo. The antitumor efficacy of LCL-CURC-DOX relied on suppressive effects on main protumor processes such as angiogenesis, inflammation, oxidative stress, invasion and resistance to apoptosis, and on the dysregulation of Th1/Th2 cell axis which favored the antineoplastic phenotype of cells in tumor microenvironment (TME). The development of multitargeted strategies aiming at stimulating antitumor effects within the tumor milieu and counteracting the escape mechanisms of cancer cells would be beneficial in the management of colon cancer in the future.

Keywords

Liposomes Curcumin Doxorubicin Drug delivery Colon cancer Tumor microenvironment 

Abbreviations

AP-1

Activator protein-1

AP-1 c-Jun

c-Jun subunit of activator protein-1

AUTC

Area under the tumor growth curve

Bcl-xL-B

Cell lymphoma-extra-large anti-apoptotic protein

Bcl-2- B

Cell lymphoma 2 anti-apoptotic protein

CURC

Curcumin

DOX

Doxorubicin

DPPC

1,2-dipalmitoyl-sn-glycero-3-phosphocholine

FBS

Fetal bovine serum

IFN-γ

Interferon γ

IL-1α

Interleukin-1α

IL-1ß

Interleukin-1ß

IL-4

Interleukin-4

IL-6

Interleukin-6

IL-10

Interleukin-10

IL-12

Interleukin-12

i.v.

Intravenous

LCL

Long-circulating liposomes

MMPs

Matrix metalloproteases

MDA

Malondialdehyde

NF-κΒ

Nuclear factor κB

NF-κΒ p65

p65 subunit of nuclear factor κB

pAP-1 c-Jun

Phosphorylated form of c-Jun subunit of AP-1

PBS

Phosphate-buffered saline

PEG

Polyethylene glycol

P-gp

P-glycoprotein

DSPE

1,2-distearoyl-sn-glycero-3 phosphoethanolamine sodium salt

pNF-κΒ p65

Phosphorylated form of p65 subunit of NF-κΒ

ROS

Reactive oxygen species

s.c.

Subcutaneous

SD

Standard deviation

TAC

Total antioxidant capacity

TBS-T

Tris-buffered saline containing 0.1% Tween-20

TME

Tumor microenvironment

Notes

Funding information

This work was supported by a grant of the Romanian National Authority for Scientific Research and Innovation, CNCS-UEFISCDI, project number PN-II-RU-TE-2014-4-0220.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving animals were in accordance with the national regulations and were approved by the Ethical Committee of the University of Medicine and Pharmacy “Iuliu Hatieganu” of Cluj-Napoca, Romania (Registration no. 371/14.10.2016 and registration no. 466/14.12.2016). All institutional and national guidelines for the care and use of laboratory animals were followed.

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Copyright information

© Controlled Release Society 2018

Authors and Affiliations

  • Alina Sesarman
    • 1
    • 2
    • 3
  • Lucia Tefas
    • 3
  • Bianca Sylvester
    • 3
  • Emilia Licarete
    • 1
    • 2
  • Valentin Rauca
    • 1
    • 2
  • Lavinia Luput
    • 1
    • 2
  • Laura Patras
    • 1
    • 2
  • Sebastian Porav
    • 1
    • 4
  • Manuela Banciu
    • 1
    • 2
    Email author
  • Alina Porfire
    • 3
  1. 1.Department of Molecular Biology and Biotechnology, Faculty of Biology and GeologyBabes-Bolyai UniversityCluj-NapocaRomania
  2. 2.Molecular Biology Centre, Institute for Interdisciplinary Research in Bio-Nano-Sciences“Babes-Bolyai” UniversityCluj-NapocaRomania
  3. 3.Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of PharmacyUniversity of Medicine and Pharmacy “Iuliu Hatieganu”Cluj-NapocaRomania
  4. 4.National Institute of R&D of Isotopic and Molecular TechnologiesCluj-NapocaRomania

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