Surface-modified cationic liposomes with a matrix metalloproteinase-degradable polyethylene glycol derivative improved doxorubicin delivery in murine colon cancer

Abstract

PEGylation is a commonly used approach to prolong the blood circulation time of cationic liposomes. However, PEGylation is associated with the "PEG dilemma", which hinders binding and uptake into tumor cells. The cleavable PEG products are a possible solution to this problem. In the current research, doxorubicin-loaded cationic liposomes (Dox-CLs) surface-conjugated with a matrix metalloproteinase-2 (MMP-2)-sensitive octapeptide linker-PEG derivative were prepared and compared to non-PEGylated and PEGylated CLs in terms of size, surface charge, drug encapsulation and release, uptake, in vivo pharmacokinetics, and anticancer efficacy. It was postulated that PEG deshielding in response to the overexpressed MMP-2 in the tumor microenvironment increases the interaction of protected CLs with cellular membranes and improves their uptake by tumor cells/vasculature. MMP2-responsive Dox-CLs had particle sizes of ∼115-140 nm, surface charges of ∼+25 mV, and encapsulation efficiencies of ∼85-95%. In vitro cytotoxicity assessments showed significantly enhanced uptake and cytotoxicity of PEG-cleavable CLs compared to their non-cleavable PEG-coated counterparts or Caelyx^®. Also, the chick chorioallantoic membrane assay showed great antiangiogenesis ability of Dox-CLs leading to target and prevent tumor neovascularization. Besides, in vivo studies showed an effective therapeutic efficacy of PEG-cleavable Dox-CLs in murine colorectal cancer with negligible hematological and histopathological toxicity. Altogether, our results showed that MMP2-responsive Dox-CLs could be served as a promising approach to improve tumor drug delivery and uptake.

Graphical Abstract

Keywords:

• Cationic liposome
• MMP-2
• doxorubicin
• angiogenesis
• cancer

Ethical approval

All animal work was approbated by the Institutional Ethical Committee and Research Advisory Committee of Mashhad University of Medical Sciences (Ethical number: IR.MUMS.SP.1396.199).

Author contributions

Investigation, Conceptualization, Methodology, Validation, Formal analysis, Writing - Original Draft, and Visualization: [Anis Askarizadeh]; Formal analysis, Methodology, Investigation, Writing - Review & Editing: [Mohammad Mashreghi]; Investigation: [Elaheh Mirhadi]; Investigation: [Amin Mehrabian]; Conceptualization, Methodology, Supervision, Writing - Review & Editing: [Vahid Heravi Shargh]; Project administration, Supervision: [Ali Badiee]; Project administration, Supervision: [Seyedeh Hoda Alavizadeh]; Project administration, Supervision: [Leila Arabi]; Methodology: [Hossein Kamali]; Conceptualization, Methodology, Supervision, Funding acquisition, Resources, Writing - Review & Editing: [Mahmoud Reza Jaafari].

Disclosure statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data availability statement

Data will be made available on request.

Additional information

Funding

This work was part of Miss Anis Askarizadeh Ph.D. thesis [grant number: 960880] supported by the Nanotechnology Research Center of the Mashhad University of Medical Sciences (MUMS). Here, we also appreciate the efforts of staff in Bu-Ali Research Institute of the MUMS, Mashhad, Iran, who provided free access to their facilities and equipment for this research.