Oxygen consumption by rapidly proliferative tumour cells results in less than ∼0.7% O2-depleted tumour areas that are known as hypoxic regions7. The pharmaceutical nanocarriers currently in use, such as liposomes, micelles and polymeric nanoparticles, among others, generally fail to reach these hypoxic regions. Combining the enhanced permeability and retention (EPR) effect of nanocarriers with longer systemic circulation properties achieved following PEGylation has increased the targeting ratio, but still results in a very limited fraction of nanocarriers entering tumours. Because only 5% of the administered nanocarriers remain in the systemic circulation after 12 h, this ultimately results in only ∼2% of the total administered dose being deposited in the tumour.
The main targeting limitations of these nanocarriers are their reliance on the systemic circulation, the lack of a propelling force to penetrate the tumour beyond their diffusion limits and the absence of a sensory-based displacement capability to target the hypoxic zones. Although robotic functionalities could correct for such deficiencies, scaling issues have prevented their integration into an artificial carrier. Harnessing a natural agent with the proper characteristics and functionalities has therefore been considered instead.