Glioma targeting peptide modified apoferritin nanocage

Therapeutic outcome for the treatment of glioma was often limited due to the non-targeted nature of drugs and the physiological barriers, including the blood-brain barrier (BBB) and the blood-brain tumor barrier (BBTB). An ideal glioma-targeted delivery system must be sufficiently potent to cross the BBB and BBTB and then target glioma cells with adequate optimized physiochemical properties and biocompatibility. However, it is an enormous challenge to the researchers to engineer the above-mentioned features into a single nanocarrier particle. New frontiers in nanomedicine are advancing the research of new biomaterials. In this study, we demonstrate a strategy for glioma targeting by encapsulating vincristine sulfate (VCR) into a naturally available apoferritin nanocage-based drug delivery system with the modification of GKRK peptide ligand (GKRK-APO). Apoferritin (APO), an endogenous nanosize spherical protein, can specifically bind to brain endothelial cells and glioma cells via interacting with the transferrin receptor 1 (TfR1). GKRK is a peptide ligand of heparan sulfate proteoglycan (HSPG) over-expressed on angiogenesis and glioma, presenting excellent glioma-homing property. By combining the dual-targeting delivery effect of GKRK peptide and parent APO, GKRK-APO displayed higher glioma localization than that of parent APO. After loading with VCR, GKRK-APO showed the most favorable antiglioma effect in vitro and in vivo. These results demonstrated that GKRK-APO is an important potential drug delivery system for glioma-targeted therapy.     

Effective encapsulation of a new cationic gadolinium chelate into apoferritin and its evaluation as an MRI contrast agent

Gd-Me₂DO2A with a T₁ proton relaxivity twice as high as that of commercial Gd-DOTA was newly designed and synthesized. Me₂DO2A kept its high association property with gadolinium ions (Gd³⁺), and the Gd-Me₂DO2A was efficiently encapsulated into the apoferritin cavity to further enhance the T₁ relaxivity as much as 10-fold higher than Gd-DOTA on a Gd basis. The high T₁ relaxivity was attained by (i) increased accessibility of water molecules to Gd³⁺ ions in the chelate and (ii) macromolecular effect of the encapsulation. By the surface modification of apoferritin with dextran, in vivo blood clearance time of apoferritin could be prolonged. Magnetic resonance imaging of tumor-bearing mice showed that the apoferritin contrast agent accomplished tumor detection effectively as a bright signal as a result of the enhanced permeation and retention effect. Single-dose toxicity test showed no serious side effects. The apoferritin-encapsulated Gd is therefore a possible candidate for a new magnetic resonance imaging contrast agent.

From the Clinical Editor

In this study by Makino et al, a novel encapsulation method of a cationic Gd chelate with apoferritin led to a proton relaxivity 10 times higher than that of standard clinically used Gd contrast dyes. If this complex passed toxicity studies, it would have an enormous clinical significance in providing a much more sensitive method to visualize BBB breakdown.     

Dragon fruit-like biocage as an iron trapping nanoplatform for high efficiency targeted cancer multimodality imaging

Natural biopolymer based multifunctional nanomaterials are perfect candidates for multimodality imaging and therapeutic applications. Conventional methods of building multimodal imaging probe require either cross-linking manners to increase its in vivo stability or attach a target module to realize targeted imaging. In this study, the intrinsic photoacoustic signals and the native strong chelating properties with metal ions of melanin nanoparticle (MNP), and transferrin receptor 1 (TfR1) targeting ability of apoferritin (APF) was employed to construct an efficient nanoplatform (AMF) without tedious assembling process. Smart APF shell significantly increased metal ions loading (molar ratio of 1:800, APF/Fe³⁺) and therefore improved magnetic resonance imaging (MRI) sensitivity. Moreover, synergistic use of Fe³⁺ and APF contributed to high photoacounstic imaging (PAI) sensitivity. AMF showed excellent bio-stability and presented good in vivo multimodality imaging (PET/MRI/PAI) properties (good tumor uptake, high specificity and high tumor contrast) in HT29 tumor because of its targeting property combined with the enhanced permeability and retention (EPR) effect, making it promising in theranostics and translational nanomedicine.     

Protein cage nanostructure as drug delivery system: magnifying glass on apoferritin

Introduction: New frontiers in nanomedicine are moving towards the research of new biomaterials. Apoferritin (APO), is a uniform regular self-assemblies nano-sized protein with excellent biocompatibility and a unique structure that affords it the ability to stabilize small active molecules in its inner core.

Areas covered: APO can be loaded by applying a passive process (mainly used for ions and metals) or by a unique formulative approach based on disassemby/reassembly process. In this article, we aim to organize the experimental evidence provided by a number of studies on the loading, release and targeting. Attention is initially focused on the most investigated antineoplastic drug and contrast agents up to the most recent application in gene therapy.

Expert opinion: Various preclinical studies have demonstrated that APO improved the potency and selectivity of some chemotherapeutics. However, in order to translate the use of APO into therapy, some issues must be solved, especially regarding the reproducibility of the loading protocol used, the optimization of nanocarrier characterization, detailed understanding of the final structure of loaded APO, and the real mechanism and timing of drug release.