Release of doxorubicin from its liposomal coating via high intensity ultrasound

Abstract

The present ex vivo study was performed to analyze the impact of high intensity ultrasound (HIUS) on penetration depth and particle stability of liposomal doxorubicin (LD) on the peritoneal surface. Fresh post mortem swine peritoneum was cut into proportional sections and subjected to a previously established ex vivo model of pressurized intraperitoneal aerosol chemotherapy (PIPAC). Samples were treated with 50 ml NaCl (0.9%) containing 3 mg LD via PIPAC or lavage. In both groups, half of the samples received additional HIUS treatment. Samples treated via PIPAC were covered with a 30-mm-thick abdominal muscle wall tissue, fatty tissue and skin, followed by transcutaneous HIUS. Samples administered with LD via lavage received close-range contact HIUS. Doxorubicin tissue penetration was measured using fluorescence microscopy on frozen sections. Liposomal integrity on peritoneal surfaces was measured via electron microscopy (EM). Mean penetration rates of doxorubicin were significantly higher with HIUS in combination with PIPAC or lavage compared with PIPAC alone (P<0.001) or lavage alone (P<0.00001). LD was not detected on the peritoneal surface via EM analysis in either group following HIUS. The present data suggested that HIUS may be a feasible application that can facilitate the release of doxorubicin from its liposomal envelope. HIUS was effective in both close-range, in contact with the samples, and through the abdominal wall. The present approach may be used in the future for both endoscopic and open lavage of the peritoneal cavity with LD in intraperitoneal chemotherapeutic applications such as hyperthermic intraperitoneal chemotherapy or PIPAC.

Intraperitoneal chemotherapy of the peritoneal surface using high-intensity ultrasound (HIUS): investigation of technical feasibility, safety and possible limitations

“…Also, no residual bleeding or other damages to the vascular intestinal structures were detected. The texture of the intestinal surface did not macroscopically change as previously reported in other models 21 . Small bowel tissue samples showed significant microscopic structural changes.…”

“…This is an especially important finding since extensive cell disruption would otherwise lead to local necrosis. The intracellular cytoskeleton might play a role in stabilizing the cell membrane, an astonishing finding considering that liposomal particles cannot withstand similar doses of HIUS 21 . The disruptive effects of HIUS seem to primarily focus on the extracellular fibers in the peritoneal tissue as well as on the muscle fiber construction of the underlying tissue.…”

“…Since the current technology offers HIUS mostly in the form of pen devices emitting ultrasonic radiation waves, it is crucial to assess possible risks of intestinal rupture by direct contact with such devices. With over two decades of application in solid tumor therapy with successful results in some cases 19 - 21 , HIUS is a promising tool which provides unique advantages including low invasiveness and absence of radiation. The aim of this study is to evaluate whether it is safe to use HIUS as a supplementary tool to prepare the abdominal cavity for IPC.…”

Overcoming Drug Resistance by Taking Advantage of Physical Principles: Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC)

“…Several studies have evaluated drug uptake into the target tissue after PIPAC, and some of them have compared PIPAC with other drug delivery techniques such as HIPEC and/or laparoscopic HIPEC. Therapeutic substances investigated include methylene blue [28,76], DNA [77], RNA [29,78], cisplatin [79][80][81][82], doxorubicin [75,[83][84][85], oxaliplatin [82,[86][87][88] and liposomal doxorubicin [89,90].…”

Increased Tissue Penetration of Doxorubicin in Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) after High-Intensity Ultrasound (HIUS)

“…In this regard, high intensity ultrasound (HIUS) has been a very promising method to potentially achieve this goal. HIUS has been investigated for over two decades in solid tumor therapy with promising results in particular cases [18][19][20]. It is already known that HIUS can improve the perfusion of chemotherapy agents in liver tumors and glioblastoma [21,22].…”