Generation of continuous production of polymeric nanoparticles via microfluidics for aerosolised localised drug delivery.

Abstract

Transferring the production of nanoparticles from laboratory batches to large-scale production for preclinical and clinical applications represents a challenge due to difficulties in scaling up formulations and lack of suitable preclinical models for testing. Here, we transpose the production of hyaluronic acid and polyarginine-based nanoparticles encapsulating the platinum-derivative dichloro(1,2 diaminocyclohexane)platinum(II), from conventional bulk method to continuous production using microfluidics. The microfluidic-based drug delivery system (DDS) is then tested in a customised preclinical setup to assess its suitability for pressurised intraperitoneal aerosol chemotherapy (PIPAC), a locoregional chemotherapy used to treat peritoneal carcinomatosis. PIPAC consists of the aerosolization of drugs under pressure using laparoscopy. In our preclinical setup, two clinical aerosol devices, CapnoPen® and TOPOL®, are used in conjunction with syringe pump to achieve the clinically optimal aerosol droplet size range (25-50 μm). Aerosol droplet sizes of 38 and 64 μm are obtained at upstream pressures of 14.7 and 7.4 bar and flow rates of 0.4 and 1.1 mL/s, for CapnoPen® and TOPOL®, respectively. To study the spatial distribution of the aerosol, our preclinical setup is then coupled to an ex-vivo model (inverted porcine urinary bladder) that mimics the physiological peritoneal cavity environment. The smaller droplet size obtained with CapnoPen® provided more homogeneous aerosol distribution in the bladder cavity, crucial for maximising treatment coverage within the peritoneal cavity. Furthermore, stability studies reveal that nanoparticles maintained their physicochemical properties and anticancer activity post-aerosolization. Overall, this study provides a scalable approach for the production of platinum-derivative-loaded polymeric nanoparticles and demonstrates the suitability of this DDS for PIPAC.