CO₂-Driven Nebulization of pH-Sensitive Supramolecular Polymers for Intraperitoneal Hydrogel Formation and the Treatment of Peritoneal Metastasis

Abstract

Because peritoneal metastasis (PM) from ovarian cancer is characterized by non-specific symptoms, it is often diagnosed at advanced stages. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) can be considered a promising drug delivery method for unresectable PM. Currently, the efficacy of intraperitoneal (IP) drug delivery is limited by the off-label use of IV chemotherapeutic solutions, which are rapidly cleared from the IP cavity. Hence, this research aimed to improve PM treatment by evaluating a nanoparticle-loaded, pH-switchable supramolecular polymer hydrogel as a controlled release drug delivery system that can be IP nebulized. Moreover, a multidirectional nozzle was developed to allow nebulization of viscous materials such as hydrogels and to reach an even IP gel deposition. We demonstrated that acidification of the nebulized hydrogelator solution by carbon dioxide, used to inflate the IP cavity during laparoscopic surgery, stimulated the in situ gelation, which prolonged the IP hydrogel retention. In vitro experiments indicated that paclitaxel nanocrystals were gradually released from the hydrogel depot formed, which sustained the cytotoxicity of the formulation for 10 days. Finally, after aerosolization of this material in a xenograft model of PM, tumor progression could successfully be delayed, while the overall survival time was significantly increased compared to non-treated animals.

Thermosensitive methyl-cellulose-based injectable hydrogel carrying oxaliplatin for the treatment of peritoneal metastasis in colorectal cancer

“…Their results demonstrated that intraperitoneal use of this nebulized hydrogelator solution successfully delayed tumor progression and significantly prolonged overall survival compared to untreated animals. 50 Hence, in future research, we intend to broaden our local intraperitoneal drug loading platform to other PM models, thereby improving the applicability of this treatment approach.…”

3D printing injectable microbeads using a composite liposomal ink for local treatment of peritoneal diseases

“…Beyond chemotherapy, these delivery systems have potential applications in preventing and treating peritoneal adhesions, a common complication of abdominal surgery [ 3 , 8 , 51 , 55 ]. By directly delivering anti-adhesion or therapeutic agents, in combination with S80, to the affected site, these systems have the ability to reduce adhesion formation and improve post-surgical outcomes as a secondary treatment [ 8 , 42 , 51 , 55 ].…”

“…The peritoneal cavity, housing key abdominal organs, is susceptible to numerous diseases including peritoneal carcinomatosis, endometriosis, and peritoneal fibrosis [ 1 ]. Current pharmacological treatments often fall short due to challenges in achieving uniform drug distribution in the peritoneal space and high clearance rates [ 1 – 3 ]. Small drug compounds, as well as drug carriers such as liposomes with a size below 1 µm, are cleared very efficiently from the peritoneum [ 4 ].…”

“…Alginate hydrogels, known for their biorthogonal and biodegradable properties, offer a solution by forming microscale systems ideal for drug delivery [ 14 – 16 ]. Incorporating liposomes in alginate microbeads results in (1) a large surface area that enhances diffusion into the target tissue, (2) potential for more uniform drug distribution due to their ease of dispersal in the peritoneal space, and (3) a particle size that evades clearance while facilitating injectability, which underscores the suitability of liposome loaded alginate microbeads for IP drug delivery [ 3 , 4 , 17 ]. The hydrogel’s coherent mesh resists the release of the liposomes, prolonging their residence in the peritoneal cavity, which in turn increases drug concentration and treatment efficacy [ 4 , 6 – 11 , 18 ].…”

Hydrogels as local depots for on-demand therapeutic delivery: potential therapeutic approaches for tumor metastasis

“…Similarly, Braet et al demonstrated a pH-sensitive hydrogel-based intraperitoneal drug delivery approach for the treatment of peritoneal metastases, which was a more promising drug delivery method for unresectable peritoneal metastases, maintaining cytotoxicity and delaying tumor growth. 94…”