Thermosensitive nanogels with multiple anti-tumour associated effects

Most chemotherapeutic treatments involve combination therapy to inhibit tumour growth, yet the systemic method of administration involving separate drug formulations results in undesirable side effects with a complicated... [ view full abstract ]

Most chemotherapeutic treatments involve combination therapy to inhibit tumour growth, yet the systemic method of administration involving separate drug formulations results in undesirable side effects with a complicated dosing strategy. Consequently, the ability to combine multiple drugs in a single nanoparticulate delivery system in which release is stimulated by external stimuli, thereby diminishing systemic effects, is of interest.
With this in mind we have explored thermosensitive microgels for their ability to change in diameter and volume in response to a change in temperature between 30 – 50°C. Within these vehicles we include gold nanoparticles, which can be used for Raman sensing or local heating, and two drugs of interest for tumour treatment, doxorubicin and pomalidomide. The effects of doxorubicin are well documented whereas pomalidomide remains a relatively novel drug that has shown promising results in the treatment of multiple myeloma (MM), among other actions including the inhibition of angiogenesis and anti-inflammatory cytokines secretion.

Gold nanoparticles, doxorubicin and pomalidomide were all entrapped within the microgels, after which positive or negatively charged polyelectrolytes were used as a coating material to stabilise the particles. In vitro experiments using single, double or unloaded microgels were conducted to assess the cytotoxic and anti-angiogenic effects of doxorubicin and pomalidomide respectively. The EPR effect of cancer cells was investigated using an in vitro mixed cell co-culture model.

Collapsed states of the microgels were observed at biological relevant temperatures which led to release of both doxorubicin and pomalidomide. Encapsulation did not affect the activity of the drugs. In vitro studies with a variety of cell lines showed high levels of microgel uptake and a slower release compared to free drug. Pomalidomide was shown to have various effects including the inhibition of LPS-induced cytokine production, disregulation of the actin cytoskeleton and inhibition of angiogenesis in tube-formation assays.

We show that these thermosensitive microgels are highly flexible tools for the encapsulation of a variety of drug or sensing compounds which importantly remain active upon release. Due to the inclusion of gold nanoparticles the microgels also can be used as sensing particles or be stimulated with light to induce local heating.