76P - Pegylated immunoliposome encapsulating docetaxel: In vitro activity and optimal pharmacokinetics in a breast cancer model

Background

Most cytotoxics used in oncology have a narrow therapeutic index, a high toxicity profile and low specific tissue diffusion to cancer cells, thus calling for the development of new delivery systems. Among these cytotoxic, docetaxel is used in combination with trastuzumab in metastatic HER2+ breast cancer (BC).

Methods

We have developed an Immunoliposome (ImmunLIPO) loaded with docetaxel and grafted with trastuzumab. The liposomes (LIPO) and ImmunLIPO formulated were then characterized in terms of size, PDI and docetaxel encapsulation rate. Antiproliferative activity was tested in human BC models ranging from near-negative (MDA-MB-231), to HER2+ (MDA-MB-453). Plasma was collected at different times after injection of ImmunLIPO (docetaxel 1,9 mg/kg and trastuzumab 160 ng/kg) or a mixture of free drugs at the same dose, into C57BL/6 mice by intraperitoneal injection.

Results

The ImmunLIPO obtained had a mean diameter of 140 nm (EPR effect distribution), a docetaxel encapsulation rate of 73% and a trastuzumab uptake rate of 400 units of trastuzumab by nanoparticle. In vitro studies on human BC cell lines demonstrated the efficacy of LIPO compared to free docetaxel (FD) (LIPO_IC50 of 5.2±2 nM or 9±4.2 nM and FD_IC50 3.6±0.4 nM or 3.9±0.5 nM for MDA-MB-231 and MDA-MB-453 cells, respectively). In vivo studies have shown superior pharmacokinetics of ImmunLIPO over FD, with a longer half-life and higher AUC (3-fold and 3.5-fold increase for the ImmunLIPO, respectively.

Conclusions

This first result suggest that ImmunoLIPO have the same characteristics in terms of in vitro properties and efficacy than FD, as well as the ability to release the encapsulated drug over time in vivo. Recent advances in the treatment of breast cancer have demonstrated the growing effectiveness of immunotherapy: enhancing immune activation and modifying the immunosuppressive microenvironment, offering patients new therapeutic options. Nanoparticles seem to be a good candidate for immune stimulation and reprogramming, allowing so-called “cold tumors” to become “hot tumors”, making it possible to use immune checkpoint inhibitors (ICI). ImmunLIPO are currently being tested as active agents in immunocompetent mice with BC in combination with ICI.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.