Paclitaxel-based DPI

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Background - Description of the Product

This ‘lung cancer cell targeting’ technology gives dry powder formulations that potentiate conventional chemotherapy by means of a dual-targeting approach, i.e. targeting lung tumour site(s) through pulmonary delivery, and lung cancer cells through targeted nanocarriers that target the folate receptor alpha (‘FR-α’, which is overexpressed by 30-50% tumours of lung cancer patients).

The invention describes:

  • (1) The use of folate-grafted polysaccharides able to bind FR-α;
  • (2) Anticancer drugs already used in the treatments of lung tumors (paclitaxel);
  • (1) and (2) as nanocarriers contained in dry powder formulations for inhalation.

These DPI formulations are composed of paclitaxel-based nanocarriers (i.e. micelles, solid lipid nanoparticles (SLN) and nanocrystals) designed to increase residence time in the lungs and aimed specifically at lung cancer cells by targeting the folate receptors. The folate receptor is overexpressed on the cancer cell surfaces in many lung tumours (i.e. more than 70% of adenocarcinomas, 30-50% of tumours of lung cancer patients) and is a promising membrane receptor to target in lung cancer. To target folate receptors, engraftment of folate groups on the nanocarrier surfaces was realized by means of folate-grafted polysaccharides.

Current results

  • The folate-grafted nanocarriers significantly increased the anti-proliferative activity of paclitaxel in vitro (up to a 6-fold increase).
  • They also improved penetration into FR-expressing lung cancer cells and tumours.
  • Folate-grafted SLN prolonged pulmonary exposure to paclitaxel to up to 6 h, with low systemic exposure following pulmonary delivery in healthy mice. This was due to their sustained-release properties (~10% paclitaxel released each 24 h in vitro) and their physicochemical characteristics (i.e. mean diameter of ~300 nm, surface modification with a mucoadhesive chitosan derivative).

  • Nanocarrier-based DPI formulations have presented good aerodynamic properties, with fine particle fractions of up to 50%. They are able to re-disperse the initial nanocarriers in physiological buffers. The powders are well-tolerated locally by heathy mice after inhalation, with no significant modification in cell composition, protein and pro-inflammatory cytokine concentration and LDH activity in broncho-alveolar lavage fluids.

  • Significantly longer survival rates were observed for the SLN inhaled treatments in combination with intravenous Taxol®, than for intravenous Taxol® alone in a lung tumour mouse model.

Relevant publications

  1. New folate-grafted chitosan derivative to improve delivery of paclitaxel-loaded solid lipid nanoparticles for lung tumor therapy by inhalation
    R. Rosière, M. Van Woensel, M. Gelbcke, V. Mathieu, J. Hecq, T. Mathivet, M. Vermeersch, P. Van Antwerpen, K. Amighi, N. Wauthoz. Mol Pharm, 15(3), 899-910 (2018)
  2. Development and evaluation of well-tolerated and tumor penetrating micelle-based dry powders for inhaled anti-cancer chemotherapy
    R. Rosière, M. Van Woensel, V. Mathieu, I. Langer, T. Mathivet, M. Vermeersch, K. Amighi and N. Wauthoz. Int. J. Pharm. 501(1-2), 148-159 (2016).
  3. New dry powders for inhalation containing chitosan derivative-coated solid lipid nanoparticles for targeted delivery to lung cancer cells
    R. Rosière, K. Amighi and N. Wauthoz, RDD Europe 2015, Vol 2, 447-452 (2015)
  4. New dry powders for inhalation containing temozolomide-based nanomicelles for improved lung cancer therapy
    R. Rosière, M. Gelbcke, V. Mathieu, P. Van Antwerpen, K. Amighi, N. Wauthoz. Int. J. Oncol., 47(3), 1131-42 (2015).
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