Current problem

Passive targeting concepts exploiting the EPR effect have not proven to significantly increase the efficacy of delivered drugs

Currently approved drugs using advanced delivery techniques for highly toxic agents such as chemotherapeutics (e.g., PEGylated liposomal doxorubicin, marketed as DOXIL®/Caelyx®) do not significantly improve efficacy (compared to systemic administration of the same drug) and only alter their side effect profile. This can be explained by two multiplicative rate-limiting steps of these delivery strategies:

  1. The nanocarriers need to extravasate into the target tissue with accumulation rates typically being <5%.
  2. If the nanocarriers extravasate into the target tissue, they are too stable such that the encapsulated API is not bioavailable.
© Thermosome
© Thermosome

The underlying Mechanism of Action of these traditional delivery techniques is called enhanced permeability and retention (EPR) effect, i.e., the idea that long-circulating nanoparticles accumulate within tumor tissue through extravasation (a way of passive targeting). Scientific studies with radioactively labeled nanocarriers in recent years have shown that only a small proportion of these nanocarriers (typically <5%) accumulate in the tumor whereas the vast majority accumulate in healthy tissue and organs, typically liver and spleen.

Moreover, even if these nanocarriers accumulate into the tumor tissue, the encapsulated drug is often not bioavailable as they are in many cases designed as very stable vehicles with half-lives of several days, which is needed to exploit the EPR effect for passive targeting. Once extravasated into the tumor, they are too stable, resulting in a significant proportion of the drug-loaded nanocarriers not releasing the encapsulated drug. Instead, the drug-loaded nanocarriers are transferred to lysosomes after cellular uptake and degraded as intact carriers prior to being able to release the encapsulated drug. As a result, only a minor proportion of the administered drug becomes active at the site of action (nuclei of tumor cells). This may explain why these nanocarrier systems commonly have not shown an improvement in therapeutic outcomes within oncological clinical studies compared to systemic administration of the same drug.