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

• Published in: Journal of liposome research 2024-06, Vol.34 (2), p.221-238
• Main Authors: Askarizadeh, Anis, Mashreghi, Mohammad, Mirhadi, Elaheh, Mehrabian, Amin, Heravi Shargh, Vahid, Badiee, Ali, Alavizadeh, Seyedeh Hoda, Arabi, Leila, Kamali, Hossein, Jaafari, Mahmoud Reza
• Format: Article
• Language: English
• Subjects: Animals; Antibiotics, Antineoplastic - administration & dosage; Antibiotics, Antineoplastic - chemistry; Antibiotics, Antineoplastic - pharmacology; Cations - chemistry; Cell Line, Tumor; Cell Survival - drug effects; Colonic Neoplasms - drug therapy; Colonic Neoplasms - pathology; Doxorubicin - administration & dosage; Doxorubicin - chemistry; Doxorubicin - pharmacology; Drug Delivery Systems; Drug Liberation; Drug Screening Assays, Antitumor; Humans; Liposomes - chemistry; Matrix Metalloproteinase 2 - metabolism; Mice; Mice, Inbred BALB C; Particle Size; Polyethylene Glycols - chemistry; Surface Properties
• ISSN: 0898-2104; 1532-2394; 1532-2394
• DOI: 10.1080/08982104.2023.2247079

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, 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%. 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, 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.