Intraperitoneal therapy for peritoneal cancer

Abstract

Cancers originating from organs in the peritoneal cavity (e.g., ovarian, pancreatic, colorectal, gastric and liver) account for approximately 250,000 new cancer cases annually in the USA. Peritoneal metastases are common owing to locoregional spread and distant metastases of extraperitoneal cancers. A logical treatment is intraperitoneal therapy, as multiple studies have shown significant targeting advantage for this treatment, including significant survival benefits in stage III, surgically debulked ovarian cancer patients. However, the clinical use of intraperitoneal therapy has been limited, in part, by toxicity, owing to the use of indwelling catheters or high drug exposure, by inadequate drug penetration into bulky tumors (>1 cm) and by the lack of products specifically designed and approved for intraperitoneal treatments. This article provides an overview on the background of peritoneal metastasis, clinical research on intraperitoneal therapy, the pharmacokinetic basis of drug delivery in intraperitoneal therapy and our development of drug-loaded tumor-penetrating microparticles.

Figure 1. Pharmacokinetic model of disposition of intraperitoneal therapy: effects of the carrier

Three formulations of paclitaxel, paclitaxel solubilized in Cremophor EL^®/ethanol (open squares), paclitaxel-loaded gelatin nanoparticles (triangles) and paclitaxel-loaded polymeric microparticles (circles) were administered by intraperitoneal injections at 10 mg/kg. For comparison, an additional group of mice received an intravenous dose of paclitaxel solubilized in Cremophor EL/ethanol (diamonds). (A) A model of kinetic processes during intraperitoneal treatment. (B & C) Paclitaxel concentration–time profiles in (B) peritoneal lavage samples and (C) plasma samples. Note the different time scales for (B) and (C). At least three mice were used for each time point. Symbols represent means ± standard deviation. *p < 0.001 compared with other groups by one-way analysis of variance with Tukey post hoc test. Reproduced with permission from [133].

Figure 2. Spatial and tissue distribution of intravenous and intraperitoneal injections of ³H-paclitaxel solubilized in Cremophor EL^®/ethanol

A mouse was administered an intraperitoneal or intravenous injection of the Cremophor formulation of paclitaxel (a mixture of radiolabeled and nonlabeled paclitaxel, equivalent to 10 mg/kg and 1 mCi/kg). (A) Whole-body section of a mouse. (B) Densitometric signals of microscale tritium standards. The numbers correspond to the relative concentrations, with the highest level set at 100%. (C) Whole-body autoradiographs at various time points after an intravenous dose. (D) Whole-body autoradiographs after an intraperitoneal dose. No radioactivity was detected in the brain following either administration route (limit of detection was 2 μg/g). (E) Relative tissue concentration–time profiles determined by digital videodensitometry after an intravenous dose (white symbols, dashed lines) or an intraperitoneal dose (black symbols, solid lines). No radioactivity was detected in the brain following either administration route. At least three mice were used for each time point. Symbols represent means ± standard deviation. Reproduced with permission from [133].

Figure 3. Scanning electron micrographs of openings and particles on the diaphragm surface

(A) Nanoparticles (660 nm diameter, arrows). (B) Microparticles (4 μm, arrows). Note that Cremophor^® micelles (13 nm, not shown) would be approximately a fiftieth of the size of the nanoparticles. Reproduced with permission from [133].

Figure 4. Intra-abdominal distribution of polymeric microparticles

(A) Distribution. Tumor-free mice were given intraperitoneal (IP) injections of rhodamine dissolved in vehicle (0.01% Tween 80 in phosphate buffer solution) plus blank microparticles (top panel) or rhodamine-labeled microparticles (bottom panel). Rhodamine appears red under ultraviolet (UV) light. (B) Effect of particle size. Tumor-free mice were administered IP injections of acridine orange-labeled microparticles with average diameters of 4 or 30 μm. Acridine orange appears yellow under UV light. The smaller particles were dispersed throughout the cavity and on mesenteric membrane and omentum, which are common sites of local metastases of ovarian tumors. The larger particles were localized in the lower abdomen and were absent on mesenteric membrane and omentum. Arrows indicate the injection sites. (C) Localization of 4-μm particles on tumors. Mice were implanted with IP human ovarian SKOV3 xenograft tumors. After tumors were established (day 42), a mouse was administered an IP dose of rhodamine-labeled microparticles. At 3 days later, the animal was anesthetized and the abdominal cavity exposed. Photographs were taken in the region of the omentum and mesentery under UV light (left panels) and room light (right panels). Note the large tumor on the omentum (~13 mm [longest diameter]) and multiple small tumors on the mesenteric membrane (1–3 mm [longest diameter]). Red color under UV light indicated localization of rhodamine-labeled particles on the tumor surface. PBS: Plant-based solvent. Reproduced with permission from [130].

Figure 5. Effect of tumor priming on spatial drug distribution in tumors: autoradiographic results

Mice bearing intraperitoneal SKOV3 tumors were administered intraperitoneal injections of either paclitaxel/Cremophor^®, priming TPMs or sustaining TPMs (all at 20 mg/kg) or two-component TPMs (40 mg/kg, 1:1 priming:sustaining). (A) TPM penetration into tumor interior. An omental tumor was removed from a mouse at 72 h after treatment with two-component TPMs and sectioned and stained with hematoxylin and eosin. The image was converted using Photoshop^®, and TPMs appeared as black dots. The top panel shows areas with clusters of TPMs (circumscribed with dotted lines). The bottom panel shows the enlarged picture of the boxed area. (B) Autoradiograms of tumor sections. (C) Concentration–depth profiles. Autoradiograms shown in (B) were processed to obtain measurements of total radioactivity using computer-assisted densitormetric analysis. Radioactivity was expressed as paclitaxel equivalents, with the highest level set at 100%. comp: Component; TPM: Tumor-penetrating microparticle. Reproduced with permission from [130].

Figure 6. Antitumor activity of tumor-penetrating microparticles

(A) Kaplan–Meier plot. (B) Distribution of time of deaths. Mice were implanted with 20 × 10⁶ SKOV3 cells intraperitoneally on day 0. At 28 days later, mice were treated with physiologic saline (control: n = 12, solid diamonds, solid line), a single dose of 40 mg/kg paclitaxel/Crem (n = 15; open circles, broken line), four doses of 10 mg/kg paclitaxel/Crem twice weekly (n = 8; open diamonds, broken line), eight doses of 15 mg/kg paclitaxel/Crem twice weekly (n = 8; open squares, broken line), a single dose of priming TPMs (40 mg/kg paclitaxel; n = 8; solid circles, solid line), a single dose of sustaining TPMs (80 mg/kg paclitaxel; n = 9; solid triangles, solid line) or a single dose of two-comp TPMs (120 mg/kg paclitaxel, 1:2 priming:sustaining; n = 9; solid squares, solid line). Two animals in single-dose paclitaxel/Crem died within 10 days after treatments and were censored. Animals remaining at the end of experiments (between 163 and 174 days) were euthanized; these include two mice in the priming TPM group, two in the sustaining TPM group, three in the two-comp TPM group and two in the eight 15 mg/kg paclitaxel/Crem dose group. None of these animals showed visible tumors in the peritoneal cavity and were considered long-term cures. Comp: Component; Crem: Cremophor; TPM: Tumor-penetrating microparticle. Reproduced with permission from [130].