Creating nanocrystallized chemotherapy: the differences in pressurized aerosol chemotherapy (PAC) via intracavitary (IAG) and extracavitary aerosol generation (EAG) regarding particle generation, morphology and structure

Abstract

Background: Nanocrystallization is a promising field for the development of new drugs. This study aims to present the use of nanocrystallization via intraperitoneal nanoaerosol therapy (INAT) for the treatment of peritoneal metastases. Methods: A continuous aerosol generation device was used to aerosolize a highly concentrated doxorubicin solution within a dry CO₂ environment. The produced nanoaerosol was directed into an ex vivo abdominal model and collision of aerosol particles with placed samples was subject to further analysis via scanning-electron microscopy (SEM). SEM detected structural changes of particles caused by migration to different locations. Results: It was possible to visualize the contact of doxorubicin aerosol particles with the surface. Larger particles as well as particles closer to the aerosol generation chamber collided with the glass sample creating liquid drops, while smaller particles with more distance to the aerosol chamber collided as highly concentrated nanocrystals. The amount of nanocrystal particles outweighed the amount of fluid aerosol particles by far. Conclusions: Under optimal conditions, the formation of nanocrystals via aerosol creation device is possible. While a wide range of possible applications of nanocrystals is conceivable, surface coating with drug particles is especially interesting as it may serve as an alternative to conventional liquid intraperitoneal chemotherapy. Further studies are required to investigate nanocrystallization of chemotherapeutic solutions as well as its physical and pharmacological properties and side effects.

Keywords: chemotherapy; electron microscopy; nanoparticles; peritoneal metastases; pressurized intra-peritoneal aerosol chemotherapy (PIPAC).

Figure 1

(A) PIPAC: model with an intracavitary aerosol generator (IAG). A continuous chemofluid is pressurized and directed through a microinjection pump which is placed in the abdominal cavity. (B) INAT: model with an extracavitary aerosol generator (EAG). A continuous air stream creates microbubbles in a liquid chemo filled cavity. As these microbubbles burst on the fluid surface, small chemo-laden aerosol particles are created and further transported with the airstream. During this airstream travel, aerosols crystallize. (C) X= 5cm, 20cm or 40 cm.

Figure 2

(A) Diameters of particles covering the glass probe after PIPAC with micropump in a 10mm2 sample area. (B) Total particle amount and size distribution on the glass probe following INAT at 40cm distance from the extracavitary aerosol generator (=” connecting tube”). Crystallized particles are illustrated in the red column. Fluid particles are illustrated in the blue column. (C) Percentual size distribution of main particle group (0 - 250nm).

Figure 3

Scanning electron microscopy (SEM) of (A) remnants of a doxorubicin aerosol particle on the glass slide created by IAG via the micropump (magnification 4575) versus (B) remnants of a doxorubicin aerosol particle and nanocrystals hitting the glass slide created by EAG (magnification 5807). Black arrows (A): 2-dimensional remnants structure of drying process of “lower” concentrated chemoaerosol particles on the glass slide. Blue arrow (B): Remnant of a “superconcentrated” chemoaerosol particle with a centralized cubic crystal. Green arrow (B): central cubic crystal. Red arrow (B): Nanocrystallized chemoparticle.

Figure 4

Scanning electron microscopy (SEM) of doxorubicin aerosol particles created by an EAG (Medisana 500®) using different lengths (X) of connecting tubes.(A) highly concentrated micro/nanoaerosol particles at X = 5 cm (magnification 3932). Green arrow: central cubic crystals within the remnant of a large size “superconcentrated” chemoaerosol particle. Yellow arrows: rim of the large size “superconcentrated” chemoaerosol particle. (B) X = 20 cm (magnification 7530). Blue arrow: Remnant of a “superconcentrated” chemoaerosol particle with a single centralized cubic crystal. (C) nanocrystals at X = 40 cm (magnification 19.958). Blue arrow: Remnant of a “superconcentrated” chemoaerosol particle with a single centralized cubic crystal. Red arrow: Nanocrystallized chemoparticle.

Figure 5

(A) Relationship between reduction in drug concentration (F(X)-axis) and increase in volume of dissolvent (X-axis) at constant dosage, demonstrated on 3 types of intraperitoneal chemotherapy. (B) Relationship between ratio of sphere volume to surface and increase in particle radius. (C) Relationship between ratio of derivatives of sphere volume to surface and increase in particle radius.