Passive versus Active Tumor Targeting Using RGD- and NGR-Modified Polymeric Nanomedicines

Abstract

Enhanced permeability and retention (EPR), and the (over-) expression of angiogenesis-related surface receptors are key features of tumor blood vessels. As a consequence, EPR-mediated passive and RGD-and NGR-based active tumor targeting have received considerable attention in the last couple of years. Using several different in vivo and ex vivo optical imaging techniques, we here visualized and quantified the benefit of RGD-and NGR-based vascular vs. EPR-mediated passive tumor targeting. This was done using ~10 nm-sized polymeric nanocarriers, which were either labeled with DY-676 (peptide-modified polymers) or with DY-750 (peptide-free polymers). Upon co-injection into mice bearing both highly leaky CT26 and poorly leaky BxPC3 tumors, it was found that vascular targeting did work, resulting in rapid and efficient early binding to tumor blood vessels, but that over time, passive targeting was significantly more efficient, leading to higher overall levels and to more efficient retention within tumors. Although this situation might be different for larger carrier materials, these insights indicate that caution should be taken not to over-estimate the potential of active over passive tumor targeting. KeywordsNanomedicine; Drug targeting; EPR; RGD; NGR Paralleled by the ever-increasing advances in nanotechnology and chemical engineering, nanomedicine formulations have started to attract significant attention in the last couple of years. Nanomedicines are 1-100(0) nm-sized carrier materials designed to improve the biodistribution and target site accumulation of low-molecular-weight (chemo-) therapeutic agents. By means of both passive and active targeting mechanisms, nanocarrier materials * Corresponding Authors Prof. Dr. Fabian Kiessling; Tel: +49-241-8080116; fkiessling@ukaachen.de Dr. Dr. Twan Lammers; Tel: +49-241-8036681; tlammers@ukaachen.de. Supporting Information Materials and methods describing the synthesis and characterization of the polymeric nanocarriers are provided as supplementary information. This material is available free of charge via the Internet at http://pubs.acs.org. Europe PMC Funders GroupAuthor Manuscript Nano Lett. Author manuscript; available in PMC 2014 March 04. Published in final edited form as:Nano Lett. 2014 February 12; 14(2): 972-981. doi:10.1021/nl404391r. Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts aim to more efficiently deliver drug molecules to pathological sites, while at the same time preventing their accumulation in potentially endangered healthy tissues, thereby beneficially affecting the balance between their efficacy and toxicity 1-4 .Passive drug targeting relies on the hyper-permeable tumor vasculature. Endothelial gaps and improperly aligned vascular endothelium result in leaky blood vessels, which enable the extravasation of carrier materials with sizes of up to several 100's of nm into the tumor interstitium. In addition to this, dysfunctional lymphatic drainage results in the retention of extravasated nanomaterials within tumo...

68 Ga-Radiolabeled AGuIX Nanoparticles as Dual-Modality Imaging Agents for PET/MRI-Guided Radiation Therapy

“…The interest of the active targeting for nanomedicine is still controversial [34,35]. For receptors present on the membrane of the tumor cells, the NPs have to be firstly accumulated in tumors by EPR effect and so active targeting will probably not drastically increase the quantity of NPs accumulated in the tumor (factor 2 or 3), as we have shown in precedent papers [36].…”

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…In healthy renal tissue, lymphatic vessels are located around large arteries and absent in the tubulointerstitium (69,70). Fibrosis is accompanied by prominent interstitial and periglomerular neolymphangiogenesis (69,70) that also occurs in renal allografts early after transplantation in humans and in animal models (71)(72)(73). This is interesting since the lymph vessels of the graft are not anastomosed to the host lymphatic vessels.…”

Characterizing EPR-mediated passive drug targeting using contrast-enhanced functional ultrasound imaging

“…We here used ~70 kDa-sized near-infrared fluorophore (NIRF) -labeled HPMA copolymers (which are known to efficiently accumulate in subcutaneous CT26 tumors in mice via EPR [29]), hybrid computed tomography-fluorescence molecular tomography (CT-FMT; [30][31][32]) and microbubble (MB) -based contrast-enhanced functional ultrasound (ceUS) imaging [33,34], to demonstrate that the degree of tumor vascularization correlates with the degree of EPR-mediated passive drug targeting. These findings indicate that relatively easily imageable vascular parameters, such as tumor blood volume and tumor blood flow, can be used to characterize EPR, and to on the basis of this preselect patients likely to respond to passively tumor-targeted nanomedicine therapies.…”

“…Clinically, however, due to the abovementioned large inter-and intraindividual variability in EPR, the efficacy of passively tumor-targeted nanomedicines is compromised, with often significant improvements in tolerability, but hardly any increases in efficacy [9,10,14]. Consequently, there seems to be a clear need to develop methods to visualize and characterize the EPR effect, in order to preselect patients presenting with sufficiently high levels of EPR, to thereby (pre-) stratify responders and non-responders, and to thereby individualize and improve nano-chemotherapeutic treatments.We here used ~70 kDa-sized near-infrared fluorophore (NIRF) -labeled HPMA copolymers (which are known to efficiently accumulate in subcutaneous CT26 tumors in mice via EPR [29]), hybrid computed tomography-fluorescence molecular tomography (CT-FMT; [30][31][32]) and microbubble (MB) -based contrast-enhanced functional ultrasound (ceUS) imaging [33,34], to demonstrate that the degree of tumor vascularization correlates with the degree of EPR-mediated passive drug targeting. These findings indicate that relatively easily imageable vascular parameters, such as tumor blood volume and tumor blood flow, can be used to characterize EPR, and to on the basis of this preselect patients likely to respond to passively tumor-targeted nanomedicine therapies.…”