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Hindawi International Journal of Surgical Oncology Volume 2019, Article ID 6185313, 6 pages https://doi.org/10.1155/2019/6185313 Research Article Increased Tissue Penetration of Doxorubicin in Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) after High-Intensity Ultrasound (HIUS) 1 2 1 1,3 Veria Khosrawipour , So¨ren Reinhard, Alice Martino , Tanja Khosrawipour, 4 5 Mohamed Arafkas, and Agata Mikolajczyk Division of Colorectal Surgery, Department of Surgery, University of California Irvine (UCI), Irvine, CA, USA Department of Bioengineering, University of California, Berkeley (UC Berkeley), Oakland, CA, USA Department of Surgery, University-Hospital Du¨sseldorf, Du¨sseldorf, North-Rhein Westfalia, Germany Department of Plastic Surgery, Ortho-Klinik Dortmund, Dortmund, North-Rhein Westfalia, Germany Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Wroclaw University of Environmental and Life Sciences, Wroclaw, Lower Silesia, Poland Correspondence should be addressed to Alice Martino; firstname.lastname@example.org Received 26 September 2019; Accepted 23 November 2019; Published 12 December 2019 Academic Editor: C.H. Yip Copyright © 2019 Veria Khosrawipour et al. +is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. High-intensity ultrasound (HIUS) has been studied for the past two decades as a new therapeutic option for solid tumor direct treatment and a method for better chemotherapy delivery and perfusion. +is treatment approach has not been tested to our knowledge in peritoneal metastatic therapy, where limited tissue penetration of intraperitoneal chemotherapy has been a main problem. Both liquid instillations and pressurized aerosols are aﬀected by this limitation. +is study was performed to evaluate whether HIUS improves chemotherapy penetration rates. Methods. High-intensity ultrasound (HIUS) was applied for 0, 5, 30, 60, 120, and 300 seconds on the peritoneal tissue samples from fresh postmortem swine. Samples were then treated with doxorubicin via pressurized intraperitoneal aerosol chemotherapy (PIPAC) under 12 mmHg and 37 C temperature. Tissue penetration of doxorubicin was measured using ﬂuorescence microscopy on frozen thin sections. Results. Macroscopic structural changes, identiﬁed by swelling of the superﬁcial layer of the peritoneal surface, were observed after 120 seconds of HIUS. Maximum doxorubicin penetration was signiﬁcantly higher in peritoneum treated with HIUS for 300 seconds, with a depth of 962.88±161.4 μm (p < 0.05). Samples without HIUS had a penetration depth of 252.25±60.41. Tissue penetration was sig- niﬁcantly increased with longer HIUS duration, with up to 3.8-fold increased penetration after 300 sec of HIUS treatment. Conclusion. Our data indicate that HIUS may be used as a method to prepare the peritoneal tissue for intraperitoneal che- motherapy. Higher tissue penetration rates can be achieved without increasing chemotherapy concentrations and preventing structural damage to tissue using short time intervals. More studies need to be performed to analyze the eﬀect of HIUS in combination with intraperitoneal chemotherapy. Various approaches have been made to improve the avail- 1. Introduction ability of chemotherapy in these tumor nodules. Peritoneal metastasis (PM) is a commonly seen manifestation For example, it has been shown that hyperthermia  of advanced gastrointestinal and gynecological cancers. It is and intraperitoneal pressure  increase drug penetration known that the antitumor eﬀect of intraperitoneal chemo- and eﬃciency. +ese concepts have already led to new therapy (IPC) is strongly limited by penetration of chemo- therapies like hyperthermic intraperitoneal chemotherapy therapy drugs well below 1mm into peritoneal nodules [1, 2]. (HIPEC) combined with cytoreductive surgery . +e 2 International Journal of Surgical Oncology application of pressure has been proposed and was ulti- was used. In the center of the top cover of the plastic box, a mately applied through pressurized intraperitoneal aerosol 5mm trocar (Kii Balloon Blunt Tip System, Applied chemotherapy (PIPAC) in the treatment of more advanced Medical, Rancho Santa Margarita, CA, USA) was placed.+e peritoneal metastasis [6, 7]. Clinical as well as experimental nozzle of the microcatheter (MC, Olympus, PW-205V studies have also tested irradiation [8–10] and new drug Olympus Surgical Technologies Europe, Hamburg, Ger- formulas [11–13] as alternate methods of increasing che- many) was introduced into the trocar. +e plastic box was motherapy penetration. Despite several attempts to improve kept at a constant temperature of 27 C during the whole penetration rates, these studies have had only limited suc- procedure. Fresh tissue specimens of peritoneum (German cess. For example, application parameters in PIPAC that landrace pigs), each measuring 4.0 ×4.0 ×0.5cm, were may aﬀect chemotherapeutic penetration depth, such as the placed at the center of the plastic box. +e distance between micropump position and dose of doxorubicin, have been the nozzle of the MC and the bottom of the plastic box was tested . Although many of these aforementioned eﬀorts 10cm. +e plastic box was then tightly sealed, and a constant have been made, penetration levels still were mostly de- CO capnoperitoneum of 12mmHg (Olympus UHI-3, scribed to be less than 500 μm [15–17]. Olympus medical life science and industrial divisions, +erefore, further methods for improved drug delivery Olympus Australia, Notting Hill, Australia) was maintained and increasing depth penetration are needed to be de- during the entire PIPAC procedure. 3mg of doxorubicin veloped. In this regard, high intensity ultrasound (HIUS) has were dissolved in 50ml NaCl 0.9% at 27 C and aerosolized. been a very promising method to potentially achieve this goal. HIUS has been investigated for over two decades in 2.3. Microscopic Analysis. After treatments, all tissue sam- solid tumor therapy with promising results in particular ples were rinsed with a sterile NaCl 0.9% solution in order to cases[18–20].Itisalready knownthatHIUS canimprovethe eliminate superﬁcial chemotherapy and immediately frozen perfusion of chemotherapy agents in liver tumors and in liquid nitrogen. Cryosections (10 μm) were prepared from glioblastoma [21, 22]. HIUS systems provide unique ad- diﬀerent areas of each specimen. Sections were mounted vantages of low invasiveness and absence of radiation. with a ProLong Gold Antifade Mountant (+ermo Fisher However, to our knowledge, its interaction in combi- Scientiﬁc) containing 1.5 μg/ml 4’,6-diamidino-2-phenyl- nation with any form of intraperitoneal chemotherapy on indole (DAPI) to stain nuclei. Penetration depth of doxo- the peritoneum has not been thoroughly investigated. It is rubicin was monitored using a Nikon Eclipse 80i known that HIUS enhances the delivery of doxorubicin in a ﬂuorescence microscope (Nikon Instruments Europe B.V. preclinical model of solid pancreatic cancer . We aimed Amsterdam, Netherlands).+edistance betweenthe luminal to evaluate its eﬀect on the penetration depth of doxorubicin surface and the innermost positive staining for doxorubicin in a well-established model of fresh postmortem peritoneal accumulation was measured and reported in micrometers. tissue samples [17, 24]. 2.4. Statistical Analyses. Experiments were independently 2. Materials and Methods performed three times. A total of eight tissue sections per 2.1. High-Intensity Ultrasound. +e experiments were per- tissue sample were subject to doxorubicin penetration mea- formed on commercially available tissue samples; hence, no surement. Prism 7.0 software (GraphPad, La Jolla, CA, USA) approval of the Local Board on Animal Care was required. was utilized to analyze the data. One-way ANOVA with a multiple comparison test wasused for analyses ofindependent Fresh postmortem swine peritoneum was purchased (local pork supplier, Zerniki Wielkie) and cut into proportional groups. A signiﬁcant p value was considered at p<0.05. sections. Samples were then placed into Petri dishes. and NaCl 0.9% was added until the peritoneal surface was 3. Results covered with 5mm of liquid. High-intensity ultrasound was 3.1. Ex Vivo Experiment. PIPAC and HIUS were applied applied with a metal pen to the center of the peritoneal tissue withoutcomplications.AfterapplyingHIUS, avisualcontrol using a sonicator (Bandelin Sonoplus, UW 2070). +e tip of of the sample was performed. No macroscopic damage of the the penwas held3mmfrom the tissue.Samples weredivided peritoneal surface was observed with shorter HIUS duration. into six groups which were treated for 0 seconds, 5 seconds, However, after 120 seconds, some whitening and swelling of 30 seconds, 60 seconds, 120 seconds, and 300 seconds, re- the peritoneum were noted. Doxorubicin was detected in spectively. Each treatment contained 0.3 seconds of active ﬂuorescence microscopy in both groups. Microscopic and 0.7 seconds of passive interval, with 20kHz frequency, analysis of the diﬀerent tissue specimens showed a sub- output power of 70W, and 50% of amplitude. stantial diﬀerence in the penetration depth of doxorubicin. Tissue penetration levels after HIUS were 361 μm±34.5 μm 2.2. Ex Vivo PIPAC Model. Samples and untreated controls at 5 seconds, 409 μm±69.7 μm at 30 seconds, were placed in a well-described ex vivo model and treated 598 μm±136.9 μm at 60 seconds, 725 μm±126.4 μm at 120 with PIPAC with doxorubicin (PFS , 2mg/ml, Pﬁzer seconds, and 962 μm±161.4 μm at 300 seconds. Controls Europe, Sandwich, United Kingdom, purity ≥98%). A without HIUS showed penetration levels with (A) commercially available hermetic sealable plastic box with a 252 μm±60.4 μm. Penetration increased signiﬁcantly with total volume of 3.5 liters, representing the abdominal cavity, longer HIUS duration (A-F vs. controls, p<0.05) and International Journal of Surgical Oncology 3 reached a maximum in the sample (F). +e penetration Doxorubicin penetration aer diﬀerent time durations of HIUS reached the 1mm level (F) and increased up to 3.8 folds to the control without HIUS (control vs. F, p<0.0001). ∗∗∗ ∗∗ +e diﬀerences between the penetration depths observed in this study summarized in Figures 1 and 2 display rep- ∗∗ resentative photos showing doxorubicin ﬂuorescence in the analyzed tissue samples. 4. Discussion In spite of progress in chemotherapeutic regimens and new 0 sec 5 sec 30 sec 60 sec 120 sec 300 sec drug compositions, poor response to systemic and local treatment is observed in a considerable part of patients, Figure 1: Tissue penetration depth of doxorubicin in μm after HIUS treatment for 0, 5, 30, 60, 120, and 300sec ( p<0.01; mainly due to molecular mechanisms and limited drug ∗∗ ∗∗∗ p<0.001; p<0.0001). distribution in the tumor [1, 25]. Pressurized intraperitoneal and pressurized intraluminal aerosol chemotherapies have been introduced to improve the treatment of advanced, multiresistant surface malignancies by overcoming limitations in drug penetration through the use of pressure and microaerosol [26, 27]. However, attempts to further improve were only partially successful, as changes of treatment parameters have only modestly improved pene- tration rates [4, 14]. Adding irradiation and modifying ap- plication modes  did not improve performance either, as penetration levels were mostlylimited to the ﬁrst few hundred microns. However, we know that increasing tissue penetra- tion enhances the antitumor eﬀect with a higher local drug disposition . In our study, we demonstrate the previously unrecognized potential of HIUS to enhance drug penetration to many folds in the peritoneal tissue. In the clinical setting, HIUS is being increasingly used as noninvasive treatment of both primary and metastatic tumors. Besides its eﬀects described here, it has addi- tional antitumor eﬀects including ablation and me- chanical disruption of cancer tissue [28, 29]. HIUS has already been shown to be useful in the treatment of uterine ﬁbroids , various solid tumors of pancreas, (a) (b) liver, renal system, and prostate, and breast cancer [31–34]. So far, there have been no or few studies for Figure 2: Microscopic analysis of the penetration depth of potential use in peritoneal metastases (PM). By im- doxorubicin into fresh peritoneal samples of German landrace pigs. proving tissue penetration, higher drug concentrations in Nuclei (blue) were stained with 4’,6-diamindino-2-phenylidole the tumor tissue could be reached without increasing the (DAPI). (a) In-tissue penetration of doxorubicin without HIUS. (b) drug dose, which is important to limit systemic side In-tissue penetration of doxorubicin after 300 seconds HIUS. eﬀects of the chemotherapy. (ePIPAC) versus PIPAC alone did not show any tissue Other attempts to improve current PIPAC and IPC increase or any other change demonstrating the eﬃcancy have been studied recently. One such attempt to improve of PIPAC by adding an electrostatic device. Additionally, overall results is synchronous intravenous chemotherapy. clinical studies could not detect any diﬀerences between Feasibility for this kind of bidirectional approach has been these two approaches in terms of biological eﬀect . demonstrated, and results on tumor regression and sur- Data on electrostatic augmentation is scarce, and the vival have been promising . However, it is unclear potential of electrostatic PIPAC is unknown. Analyzing whether this eﬀect is predominantly that of PIPAC or the eﬀects of electrostatic precipitation combined with the rather one of the intravenous chemotherapies. Studies applied aerosol itself is quite a challenge, and while on- indicate that this might be an eﬀect of PIPAC , while going studies present new locations and various appli- the eﬀect of the additional intravenous chemotherapy is cations for chemoaerosol [39, 40], there is an ongoing unknown. eﬀort to understand the applied chemoaerosol itself Another attempt to improve PIPAC was the in- [39, 41]. troduction of electrostatic precipitation as an additional +e application of heat in IPC is well studied. Heat has feature to the procedure. A recent study from Giger-Pabst shown to increase cytotoxicity and has therefore been an et al.  analyzing the eﬀect of electrostatic PIPAC Doxorubicin penetration in µm 4 International Journal of Surgical Oncology integral part in HIPEC . However, the application of was involved in study design, laboratory analysis, data ac- heat in PIPAC is a technical challenge because heat would quisition, and manuscript drafting. MA was involved in data have to be distributed through the applied gaseous capno- interpretation and critical revision for important intellectual peritoneum. +erefore, it remains unclear if heat has a role content of the manuscript. AM was responsible for super- in PIPAC. Despite these limitations, concepts based on basic vision of the study, drafting, and critical revision for im- physical principles like heat, electrostatic eﬀects, changing portant intellectual content of the manuscript. physical properties of applied substances , or mechanic alteration  of the biological surface have gained more Acknowledgments interest recently as they seem to have more potential than initially expected. +is study was funded by Institutional Funds. Our data indicate that HIUS plus PIPAC can overcome the 1mm barrier on the peritoneum, which is a very References promising result. HIUS resulted in better penetration of doxorubicin into swine peritoneum samples from 1.4 to 3.8  R. L. Dedrick, C. E. 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