Liposomal Tumor Targeting in Drug Delivery Utilizing MMP-2- and MMP-9-Binding Ligands

Abstract

Nanotechnology offers an alternative to conventional treatment options by enabling different drug delivery and controlled-release delivery strategies. Liposomes being especially biodegradable and in most cases essentially nontoxic offer a versatile platform for several different delivery approaches that can potentially enhance the delivery and targeting of therapies to tumors. Liposomes penetrate tumors spontaneously as a result of fenestrated blood vessels within tumors, leading to known enhanced permeability and subsequent drug retention effects. In addition, liposomes can be used to carry radioactive moieties, such as radiotracers, which can be bound at multiple locations within liposomes, making them attractive carriers for molecular imaging applications. Phage display is a technique that can deliver various high-affinity and selectivity peptides to different targets. In this study, gelatinase-binding peptides, found by phage display, were attached to liposomes by covalent peptide-PEG-PE anchor creating a targeted drug delivery vehicle. Gelatinases as extracellular targets for tumor targeting offer a viable alternative for tumor targeting. Our findings show that targeted drug delivery is more efficient than non-targeted drug delivery.

Matrix-metalloproteinases as targets for controlled delivery in cancer: An analysis of upregulation and expression

“…Once such targeting peptide is cyclic peptide inhibitor (CTT), CTTHWGFTLC, which binds specifically as an inhibitor to the gelatinases, MMP-2 and MMP-9. CTT has been used to enhance the delivery of liposomes and protein nanocages compared to non-targeted vessels in vivo in murine cancer models[196–199]. Given the peptidic nature of CTT, it can also be seamlessly grafted onto biologics to enhance their accumulation in rapidly growing tumors[200].…”

“…In a study of five human patients, however, the tracer was shown to predominantly distribute to the kidneys with no distinguishable signal in other tissues, casting doubt on TIMP effectiveness for localization of drugs to tumors[208]. Several labs have combined targeting elements for other targets, such as CD44[209] or HER2[210], with MMP-cleavable linkers that function as secondary selection factor to trigger drug release or activate cell penetrating peptides after tumor accumulation[199,211,212]. However, as these particles used MMP-cleavable linkers rather than binding peptides, they are considered to use MMP-cleavage as their mode of targeting for the purpose of this review [See MMP-Cleavage from Nanocarriers].…”

Nanomedicines for cancer therapy: state-of-the-art and limitations to pre-clinical studies that hinder future developments

“…Targeted delivery systems used in quantitative pre-clinical studies include silica (Benezra et al, 2011 ; Tang et al, 2012 ; Chen et al, 2013 ), gold (Melancon et al, 2008 ; Lu et al, 2009 , 2010 ; Chanda et al, 2010 ; Choi et al, 2010 ; Morales-Avila et al, 2011 ; Chattopadhyay et al, 2012 ), liposomes (Iyer et al, 2011 ; Helbok et al, 2012 ; Petersen et al, 2012 ), micelles (Hu et al, 2008 ; Penate Medina et al, 2011 ; Zhang et al, 2011b ; Fonge et al, 2012 ; Helbok et al, 2012 ) (Rossin et al, 2005 ; Khemtong et al, 2009 ; Zhan et al, 2010 ; Poon et al, 2011 ; Zhang et al, 2011a ; Xiao et al, 2012 ), iron oxide (Natarajan et al, 2008 ; Kumar et al, 2010 ; Yang et al, 2011 ), graphene (Hong et al, 2012 ; Cornelissen et al, 2013 ; Shi et al, 2013 ), gadolinium (Oyewumi et al, 2004 ), polymer nanocarriers (Kunjachan et al, 2014 ), nanoemulsions (Ohguchi et al, 2008 ), quantum dots (Gao et al, 2010 ), and hybrid (Cheng et al, 2014 ) (Supplementary Table S2 ). Similar to passive targeting, few studies (3/34) report %ID rather than %ID/g.…”

Nuclear Medicine in Finland

“…[21] This invention led to multiple inventions of creating multi-potential intelligent targeted nanoparticles for drug delivery. [22] Radioimmunotherapy was also applied clinical pediatric oncology, e.g., for treating hepatoblastoma. [23] Peptide receptor therapy was initiated in Finland in 2000, and practical 4-D dosimetry routine applications of Lu-177 treatments was introduced in 2010.…”