Specific Targeting of PEGylated Liposomal Doxorubicin (Doxil®) to Tumour Cells Using a Novel TIMP3 Peptide

Abstract

Doxorubicin is a cytotoxic anthracycline derivative that has been used as a chemotherapeutic in many different forms of human cancer with some success. However, doxorubicin treatment has several side-effects, the most serious of which is cardiomyopathy, that can be fatal. Doxorubicin encapsulation in PEGylated liposomes (Doxil®) has been shown to increase tumour localisation and decrease cardiotoxicity. Conversely, the stability of such liposomes also leads to increased circulation times and accumulation in the skin, resulting in palmar planter erythrodysesthesia, while also limiting release of the drug at the tumour site. Specific targeting of such liposomes to tumour cells has been attempted using various receptor-specific peptides and antibodies. However, targeting a single epitope limits the likely number of tumour targets and increases the risk of tumour resistance through mutation. In this report, Doxil® was coupled to peptide sequence p700 derived from tissue inhibitor of metalloproteinase 3. This Doxil® -P700 complex results in an approximately 100-fold increase in drug uptake, relative to Doxil® alone, by both mouse and human breast cancer cells and immortalised vascular cells resulting in an increase in cytotoxicity. Using p700 to target liposomes in this way may enable specific delivery of doxorubicin or other drugs to a broad range of cancers.

Recent Preclinical and Clinical Progress in Liposomal Doxorubicin

“…These approaches are gaining more interest as a promising strategy to enhance the efficacy of liposomal delivery [ 35 ]. These molecules are usually conjugated to the terminal end of the PEG chain and serve (except CPEs) as ligands for overexpressed targets on the surface of the cancer cells, increasing the specific accumulation of PLD in the tumor [ 36 , 37 ].…”

A mini-review of Nanocarriers in drug delivery systems

“…This could also be potentially problematic due to slowing the drug release rate, decreasing cytotoxic effects and an increase in liposomal accumulation in skin cells causing hand-foot syndrome (Tse.g., Liu, & Hong, 2002) (Patil, Guhagarkar, & Devarajan, 2008). Aldughaim et al (2020) formulated a targeted PLD system (Doxil ® -P700 complex) by coupling 16-amino acid peptide from tissue inhibitor of metalloproteinase 3 (TIMP3) to the liposomal surface (Aldughaim, Muthana, Alsaffar, & Barker, 2020). This was to specifically target proangiogenic tyrosine kinase receptors.…”

Biophysical Characterization of (DOX-NPtm): FTIR and DSC Studies

“…It has fewer side effects on healthy cells than doxorubicin. It is approved by the FDA, and is currently used to treat recurrent ovarian cancer and Kaposi's sarcoma [12,13]. The biophysical characterization of this marketed DOX-NP TM formulation was investigated in this work.…”