Protein nanocages that penetrate airway mucus and tumor tissue

Abstract

Reports on drug delivery systems capable of overcoming multiple biological barriers are rare. We introduce a nanoparticle-based drug delivery technology capable of rapidly penetrating both lung tumor tissue and the mucus layer that protects airway tissues from nanoscale objects. Specifically, human ferritin heavy-chain nanocages (FTn) were functionalized with polyethylene glycol (PEG) in a unique manner that allows robust control over PEG location (nanoparticle surface only) and surface density. We varied PEG surface density and molecular weight to discover PEGylated FTn that rapidly penetrated both mucus barriers and tumor tissues in vitro and in vivo. Upon inhalation in mice, PEGylated FTn with optimized PEGylation rapidly penetrated the mucus gel layer and thus provided a uniform distribution throughout the airways. Subsequently, PEGylated FTn preferentially penetrated and distributed within orthotopic lung tumor tissue, and selectively entered cancer cells, in a transferrin receptor 1-dependent manner, which is up-regulated in most cancers. To test the potential therapeutic benefits, doxorubicin (DOX) was conjugated to PEGylated FTn via an acid-labile linker to facilitate intracellular release of DOX after cell entry. Inhalation of DOX-loaded PEGylated FTn led to 60% survival, compared with 10% survival in the group that inhaled DOX in solution at the maximally tolerated dose, in a murine model of malignant airway lung cancer. This approach may provide benefits as an adjuvant therapy combined with systemic chemo-or immunotherapy or as a stand-alone therapy for patients with tumors confined to the airways. lung cancer | nanoparticle | biological barriers | PEG | human ferritin

Thirty Years of Cancer Nanomedicine: Success, Frustration, and Hope

“…Recent concerns about possible non-specific interactions of iRGD that might reduce the target accumulation of NCs could be overcome by triggering the penetrating peptide exposure in the TME following specific stimuli [49]. Another common approach to minimize the interaction between NCs and the ECM is surface PEGylation, as has been demonstrated in different tumor models, such as orthotopic brain and lung cancers [50,51]. However, a dense PEG layer may discourage interaction with target cells.…”

Red blood cell-hitchhiking boosts delivery of nanocarriers to chosen organs by orders of magnitude

“…This IA-based extension of RH, if successful, would demonstrate the synergistic power of combining nanomedicine with different size-scale technologies; here, we employed the synergistic combination of “nano-micro-macro”: nano-scale drug carriers + micro-scale RBCs + macro-scale IA catheters. The synergy of nano-micro-macro has recently been productively leveraged for other NC and gene therapy delivery challenges, such as intraperitoneally injected NCs that stick to mesothelial cells to act as a drug depot 15 , peri-nerve injections of NCs to block pain 16 , intratracheally administered NCs that localize near airway epithelial cells 17 , 18 , NCs injected into the brain parenchyma to land on neurons or tumor cells 19 – 21 , and delivery of gene therapy vehicles to overcome similar barriers 22 , 23 . Building off these prior approaches, the particular nano-micro-macro synergy of RH, if successful, could provide localized, high-concentration drug delivery to any organ into which an intravascular catheter can be clinically deployed.…”

Engineered Human Nanoferritin Bearing the Drug Genz-644282 for Cancer Therapy

“…Protein-cage molecules based on the H-chain of human ferritin (HFt) have been recently attracting growing interest in the field of cancer drug delivery, due to their excellent biocompatibility, selectivity for cancer over normal cells, binding to a large number of different human tumors and ability to encapsulate in their internal cavity high amounts (20–120 molecules) of different drug classes [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. The cage-like shape is due to the fact that HFt is a multimeric protein consisting of 24 identical subunits that self-assembly into a symmetric hollow sphere, with external and internal diameters of 12 and 8 nm, respectively [ 15 , 16 , 17 , 18 ].…”