Aerosolization of nanotherapeutics as a newly emerging treatment regimen for peritoneal carcinomatosis

Recent advances in locoregional chemotherapy have opened the door to new approaches for the clinical management of peritoneal carcinomatosis (PC) by facilitating the delivery of anti-neoplastic agents directly to the tumor site, while mitigating adverse effects typically associated with systemic administration. In particular, an innovative intra-abdominal chemotherapeutic approach, known as Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC), was recently introduced to the intraperitoneal (IP) therapy regimens as a palliative therapeutic option in patients with PC, presumably providing a better drug distribution pattern together with deeper drug penetration into tumor nodules within the peritoneal space. Furthermore, the progress of nanotechnology in the past few decades has prompted the application of different nanomaterials in IP cancer therapy, offering new possibilities in this field ranging from an extended retention time to sustained drug release in the peritoneal cavity. This review highlights the progress, challenges, and opportunities in utilizing cancer nanotherapeutics for locoregional drug delivery, with a special emphasis on the aerosolization approach for intraperitoneal therapies

Nanomedicine-based intraperitoneal therapy for the treatment of peritoneal carcinomatosis : mission possible?

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Establishment of a rat ovarian peritoneal metastasis model to study pressurized intraperitoneal aerosol chemotherapy (PIPAC)

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Synergy between intraperitoneal aerosolization (PIPAC) and cancer nanomedicine : cisplatin-loaded polyarginine-hyaluronic acid nanocarriers efficiently eradicate peritoneal metastasis of advanced human ovarian cancer

Intra-abdominal dissemination of peritoneal nodules, a condition known as peritoneal carcinomatosis (PC), is typically diagnosed in ovarian cancer patients at the advanced stages. The current treatment of PC consists of perioperative systemic chemotherapy and cytoreductive surgery, followed by intra-abdominal flushing with solutions of chemotherapeutics such as cisplatin and oxaliplatin. In this study, we developed cisplatin-loaded polyarginine-hyaluronic acid nanoscale particles (Cis-pARG-HA NPs) with high colloidal stability, marked drug loading efficiency, unimpaired biological activity, and tumor-targeting ability. Injected Cis-pARG-HA NPs showed enhanced antitumor activity in a rat model of PC, compared to injection of the free cisplatin drug. The activity of Cis-pARG-HA NPs could even be further improved when administered by an intra-abdominal aerosol therapy, referred to as pressurized intraperitoneal aerosol chemotherapy (PIPAC). PIPAC is hypothesized to ensure a more homogeneous drug distribution together with a deeper drug penetration into peritoneal tumor nodules within the abdominal cavity. Using fluorescent pARG-HA NPs, this enhanced nanoparticle deposit on tumors could indeed be observed in regions opposite the aerosolization nozzle. Therefore, this study demonstrates that nanoparticles carrying chemotherapeutics can be synergistically combined with the PIPAC technique for IP therapy of disseminated advanced ovarian tumors, while this synergistic effect was not observed for the administration of free cisplatin

Electrostatic precipitation is a valuable adjunct to pressurized intraperitoneal aerosol chemotherapy : an in vitro study

BACKGROUND: Peritoneal metastasis (PM) is a frequent manifestation of gastro-intestinal and gynaecological cancer. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) was recently introduced for the treatment of irresectable PM, with promising anticancer activity and adequate tolerance. Adding electrostatic force (i.e. 7.5 – 9.5 kV; a current of ≤ 10 µA) to aerosolized particles could further enhance the pharmacologic properties of PIPAC. This procedure is termed electrostatic precipitation PIPAC or ePIPAC. This in vitro study investigated if ePIPAC could lead to a more homogeneous distribution of the drug and an increased penetration depth, enhancing the efficacy of PIPAC. MATERIALS AND METHODS: Black ink was nebulized (PIPAC n=6; ePIPAC n=6) in an in vitro box model containing fresh swine omentum on four different locations: on the bottom of the box (A), under a bilaterally open plastic tunnel (B), on the side wall of the box (C) and on the top of the box (D). The proportion (%) black ink in each specimen was macroscopically measured by ImageJ. The specimens were then embedded and cryosections (20 µm) were made. Each cryosection was scored by three independent observers for the amount of ink visible on the tissue surface using a light microscope: 0 = no ink visible; 0.5 = hardly visible line; 1 = clear line visible. To evaluate the penetration depth after PIPAC and ePIPAC, carboxylate-modified red fluorescent microspheres of 0.1 µm were nebulized (PIPAC n=6; ePIPAC n=6) in the in vitro box. The penetration depth of the microspheres was measured by confocal fluorescence imaging. RESULTS: No significant differences of the stained proportion of the specimens were found at location A (99 ± 1% vs. 98 ± 2%) and B (98 ± 2% vs. 96 ± 4%) in PIPAC and ePIPAC, respectively. Strikingly, a significant (p=0.015) increase was found in location C (68 ± 27% vs. 93 ± 9%) and D (23 ± 35% vs. 84 ± 30%) after ePIPAC, indicating a more homogeneous distribution pattern. These findings were in accordance with the mean cryosection scores: histological ink staining did not differ on location A (0.89 ± 0.17 vs. 1 ± 0.00) and B (0.89 ± 0.20 vs. 0.94 ± 0.09) after PIPAC and ePIPAC, respectively. However, specimens on locations C (0.39 ± 0.33 vs. 0.94 ± 0.09; p=0.0065) and D (0.22 ± 0.36 vs. 0.78 ± 0.20; p=0.022) were significantly more stained after ePIPAC than after PIPAC. Results regarding the penetration depth of the fluorescently labelled microspheres will also be presented. CONCLUSIONS: The addition of electrostatic precipitation to PIPAC significantly enhances aerosol distribution pattern in an in vitro box model. Consequently, ePIPAC may allow more homogeneous and efficient drug uptake, and improve the management of irresectable PM. At the same time, ePIPAC may allow to use a lower drug dose, and lead to less side effects

Bioinspired hyaluronic acid and polyarginine nanoparticles for DACHPt delivery

International audienceThis work provides insights over a novel biodegradable polymeric nanosystem made of hyaluronic acid and polyarginine for diaminocyclohexane-platinum (DACHPt) encapsulation. Using mild conditions based on ionic gelation technique, monodispersed blank and DACHPt-loaded nanoparticles (NP) with a size of around 200 nm and negative ζ potential (-35 mV) were obtained. The freeze-drying process was optimized to improve the stability and shelf-life of the developed nanoparticles. After reconstitution, nanoparticles maintained their size showing an association efficiency of around 70 % and a high drug loading (8%). In vitro cytotoxicity studies revealed that DACHPt-loaded nanoparticles had a superior anticancer activity compared with oxaliplatin solution. The IC50 was reduced by a factor of two in HT-29 cells (IC50 39 µM vs 74 µM, respectively), and resulted almost 1.3 fold lower in B6KPC3 cells (18µM vs 23µM respectively). Whereas toxic effects of both drug and DACHPt-loaded nanoparticles were comparable in the A549 cell line (IC50 11 µM vs 12 µM). DACHPt-loaded nanoparticles were also able to modulate immunogenic cell death (ICD) in vitro. After incubation with B6KPC3 cells, an increase in HMGB1 (high-mobility group box 1) production associated with ATP release occurred. Then, in vivo pharmacokinetic studies were performed after intravenous injection (IV) of DACHPt-loaded nanoparticles and oxaliplatin solution in healthy mice (35.9 µg of platinum equivalent/mouse). An AUC six times higher (24 h*mg/L) than the value obtained following the administration of oxaliplatin solution (3.76 h*mg/L) was found. Cmax was almost five times higher than the control (11.4 mg/L for NP vs 2.48 mg/L). Moreover, the reduction in volume of distribution and clearance clearly indicated a more limited tissue distribution. A simulated repeated IV regimen was performed in silico and showed no accumulation of platinum from the nanoparticles. Overall, the proposed approach discloses a novel nano-oncological treatment based on platinum derivative with improved antitumor activity in vitro and in vivo stability as compared to the free drug

Electrostatic intraperitoneal aerosol delivery of nanoparticles : proof of concept and preclinical validation

There is an increasing interest in intraperitoneal delivery of chemotherapy as an aerosol in patients with peritoneal metastasis. The currently used technology is hampered by inhomogenous drug delivery throughout the peritoneal cavity because of gravity, drag, and inertial impaction. Addition of an electrical force to aerosol particles, exerted by an electrostatic field, can improve spatial aerosol homogeneity and enhance tissue penetration. A computational fluid dynamics model shows that electrostatic precipitation (EP) results in a significantly improved aerosol distribution. Fluorescent nanoparticles (NPs) remain stable after nebulization in vitro, while EP significantly improves spatial homogeneity of NP distribution. Next, pressurized intraperitoneal chemotherapy with and without EP using NP albumin bound paclitaxel (Nab-PTX) in a novel rat model is examined. EP does not worsen the effects of CO(2)insufflation and intraperitoneal Nab-PTX on mesothelial structural integrity or the severity of peritoneal inflammation. Importantly, EP significantly enhances tissue penetration of Nab-PTX in the anatomical regions not facing the nozzle of the nebulizer. Also, the addition of EP leads to more homogenous peritoneal tissue concentrations of Nab-PTX, in parallel with higher plasma concentrations. In conclusion, EP enhances spatial homogeneity and tissue uptake after intraperitoneal nebulization of anticancer NPs