Combined Delivery and Magnetic Resonance Imaging of Neural Cell Adhesion Molecule–Targeted Doxorubicin-Containing Liposomes in Experimentally Induced Kaposi's Sarcoma

Abstract

Specific targeting of tumors by combined delivery of drugs and of imaging agents represents an attractive strategy for treatment of cancer. The aim of the present study was to investigate whether neural cell adhesion molecule (NCAM)-targeted liposomes may enhance drug delivery and allow magnetic resonance imaging (MRI) in a severe combined immunodeficient mouse model of NCAM-positive Kaposi's sarcoma. NCAM-binding peptide-coated liposomes loaded with both doxorubicin and a lipophilic gadolinium (Gd) derivative were generated. NCAM-targeted liposomes induced an enhanced in vitro doxorubicin internalization within Kaposi's cells as detected by MRI with respect to untargeted polyethylene glycol liposomes. Internalization resulted in enhanced apoptosis. In vivo weekly administration of NCAM-targeted liposomes containing 5 mg/kg doxorubicin for 4 consecutive weeks induced a significant reduction of tumor mass and vascularization and enhanced cell necrosis and apoptosis with respect to untargeted liposomes. These effects were associated with an enhanced concentration of doxorubicin within the tumor and a reduced systemic toxicity of doxorubicin. By electron microscopy, NCAM-targeted liposomes were detected mainly within tumor cells whereas the untargeted liposomes were mainly accumulated in the extracellular space. Gd-labeled liposomes allowed the MRI visualization of drug delivery in the tumor region. The intensity of MRI signal was partially hampered by the "quenching" of the attainable relaxation enhancement on endosomal entrapment of the Gd-labeled liposomes. In conclusion, targeting NCAM may be a suitable strategy for specific drug delivery and imaging by liposomes in NCAM-expressing tumors. Moreover, treatment with NCAM-targeted liposomes showed enhanced therapeutic effect and reduced toxicity with respect to untargeted liposomes. Cancer Res; 70(6); 2180-90. ©2010 AACR.

Folate-Targeted Gadolinium-Lipid-Based Nanoparticles as a Bimodal Contrast Agent for Tumor Fluorescent and Magnetic Resonance Imaging

“…The internalization of paramagnetic NPs into cells was believed to limit the attainable relaxation enhancement as a consequence of the reduced water exchange across the barriers among the cellular compartments. 49) However, F(5000)-NPs exhibited a higher 24-h postinjection/preinjection signal intensity enhancement ratio in tumors than that exhibited by NPs (Fig. 5).…”

Bridging the Knowledge of Different Worlds to Understand the Big Picture of Cancer Nanomedicines

“…[69] Similarly, targeted theranostic liposomes consisting of gadolinium and doxorubicin with peptide targeted to neural cell adhesion molecules showed high drug concentration in tumors, inhibiting the tumor growth with enhanced MRI imaging of Kaposi's tumours in mice. [70] Moreover, porous silica coated quantum dots loading doxorubicin can spontaneously achieve cathepsin B enzyme targeting drug release and real-time fluorescence imaging in lung carcinoma A549 cells. [71] Recently, an advanced targeted and multi-stimuli responsive of a theranostic nanosystem consisting of pH-responsive polymeric-drug conjugate, iron oxide nanoparticles and conjugated with a tumor homing iRGD peptide was developed for the intracellular triggered delivery of doxorubicin targeted to endothelial and metastatic cancer cells.…”

“…[22,143,144] Although, increasing number of nanomedicines have been reported based on the EPR principle, it is often over simplified and unified virtually for all type of tumors, whereas it is substantially more complex in reality. [145] In murine cancer models, polymeric micelles with different sizes (30,50,70, and 100 nm) showed similar extravasation and anti-tumor activities in highly permeable colon adenocarcinoma, whereas in less permeable pancreatic tumors, only polymeric micelles with 30 nm size in diameter showed significant tumor accumulation. [146] Similarly, in another preclinical study, the tumor type dependent EPR effect was reported in carcinomas and sarcomas with a heterogeneous uptake level of liposomes.…”

Theranostic Probes for Targeting Tumor Microenvironment: An Overview

“…On the other hand, the PEG liposome was accumulated extracellularly. The doxorubicin drug release was observed through MRI by tagging the liposome with a gadolinium-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) -monoamide or Gd DOTAMA (C18)2 in short [57]. Gd DOTAMA, an important contrast agent, is capable of determining specific signatures of the TME.…”