Effects of particle size and release property of paclitaxel-loaded nanoparticles on their peritoneal retention and therapeutic efficacy against mouse malignant ascites

https://doi.org/10.1016/j.ijpharm.2022.121904Get rights and content

Highlights

  • 1000 nm liposomes highly retained in peritoneal cavity.

  • 100 nm nanoparticles rapidly transferred from peritoneal cavity to blood.

  • Incomplete drug release causes the low therapeutic effect of liposomes.

  • Emulsions showed anti-tumor efficacy owing to their adequate stability.

Abstract

Malignant ascites accounts for abdominal pain, dyspnea and anorexia, all of which decrease quality of life in cancer patients. Intraperitoneal chemotherapy is a useful method for managing malignant ascites and nanoparticulate drug delivery system makes it more effective by increasing peritoneal retention of anti-cancer drugs. In this study, we prepared paclitaxel-loaded emulsions and liposomes with different particle sizes and drug release properties, and evaluated their peritoneal retention and therapeutic efficacy in Ehrlich’s ascites carcinoma (EAC)-bearing mice. Liposomes with the size of 100 nm were rapidly absorbed from peritoneal cavity into blood after intraperitoneal injection into EAC-bearing mice, whereas 1000-nm liposomes were highly retained in peritoneal cavity. Accordingly, 1000 nm liposomes significantly prolonged survival time of EAC-bearing mice but did not inhibit the ascites accumulation because of too poor paclitaxel release. On the other hand, although peritoneal retention of emulsions themselves was similar irrespective of their sizes, 270-nm emulsions showed the higher PTX retention in ascites than other emulsions, and resulted in significantly prolonged survival time and lower accumulation of ascites in EAC-bearing mice. These results indicate that not only particle size but drug release property is one of key determinants of the biodisposition and therapeutic efficacy of intraperitoneally injected nanoparticulate PTX against malignant ascites.

Introduction

Malignant ascites (MA) is a pathological condition which often leads to the accumulation of ascites in the peritoneal cavity in cancer patients. Increased permeability of tumor vessel and obstructed lymphatic drainage are considered to be the main factors in MA development, and ovarian, colorectal, pancreatic, gastric cancers and peritoneal malignancy are sometimes accompanying MA (Cavazzoni et al., 2013, Hodge and Badgwell, 2019). MA accounts for a variety of symptoms, including abdominal pain, dyspnea, anorexia, nausea, impaired movement, and fatigue, all of which compromise quality of life (QOL) and activities of daily living in patients. In addition, MA is recognized as a poor prognostic indicator (Kim et al., 2016, Hodge and Badgwell, 2019).

Intraperitoneal chemotherapy is useful for managing MA and for the better QOL of patients. Compared with systemic chemotherapy, intraperitoneal chemotherapy is capable of increasing the concentration of anti-cancer drugs in peritoneal cavity, and consequently achieving longer exposure of anti-cancer drugs to cancer cells (Kitayama, 2014, Sarfarazi et al., 2019). Several anti-cancer drugs, such as cisplatin, doxorubicin and paclitaxel (PTX), have been clinically used in intraperitoneal chemotherapy (Yan et al., 2006, Yan et al., 2007, Ansaloni et al., 2012). In particular, intraperitoneal administration of PTX showed promising clinical outcomes in patients with gastric cancer and pancreatic cancer with MA (Yamaguchi et al., 2013, Takahara et al., 2016, Yamada et al., 2020). However, since these anti-cancer drugs peritoneally injected are rapidly eliminated from peritoneal cavity (Sadzuka et al., 1997, Abuzar et al., 2020), the development of new approach to maintain the effective concentration of these anti-cancer drugs in the peritoneal cavity is strongly awaited for the better therapeutic outcome.

It is well known that the retention pattern of therapeutics at the injected site largely depends on their sizes (Carstens et al., 2011, Sarfarazi et al., 2019, Joseph et al., 2020). For example, small molecules are generally eliminated from the injected site via blood vessels whereas large molecules (approximately larger than 10 nm) are preferentially cleared from lymphatic capillaries (Cai et al., 2011, Ryan et al., 2014). Since the flow rate of lymph fluid is considerably lower than that of blood, large molecules have higher retention capacity at the injected site than small molecules (Cai et al., 2011, Ryan et al., 2014). Based on these information, nanoparticulate drug delivery system, such as emulsions and liposomes, would be one of the promising technologies to control the concentration–time profiles of anti-cancer drugs in peritoneal cavity. We have previously demonstrated that PTX-loaded emulsions with the size of 100 nm exhibit significantly more efficient therapeutic effect against mouse MA than PTX solution, resulting in the marked prolongation of survival of mouse with MA (Ogawara et al., 2017). We considered that this would be due to the longer maintenance of PTX concentration at higher level in peritoneal cavity by encapsulating PTX in emulsions. However, the substantial impact of the particle size of PTX-loaded emulsions on their peritoneal retention and therapeutic efficacy against MA after intraperitoneal injection is still unclear.

Therefore, in this study, we prepared three PTX-loaded emulsions with different particle sizes, and assessed their in vitro PTX release properties, in vivo disposition and therapeutic efficacy in mouse with MA. In addition, since we have previously demonstrated that liposomes could incorporate PTX more stably than emulsions (Yoshizawa et al., 2011), PTX-loaded liposomes with two different particle sizes were also prepared and assessed.

Section snippets

Animals

Male ddY mice (6 weeks old) were purchased from Charles River Laboratories Japan (Yokohama, Japan). All animal experiments were carried out in accordance with the Guide for the Care and Use of Laboratory Animals, as approved and promulgated by the U.S. National Institutes of Health (Bethesda, MD, USA) and the Guidelines for Animal Experiments of Okayama University (Okayama, Japan). The protocol was approved by the local ethics committee at Okayama University. All efforts were made to minimize

Physicochemical properties of PTX-loaded emulsions and liposomes

In this study, we prepared three PTX-loaded emulsions and two PTX-loaded liposomes with different particle sizes. The physicochemical properties of these PTX-loaded nanoparticles are listed in Table 2. We attempted to control the particle size of emulsions by adjusting the mixing amounts of emulsifying agents (Table 1) and the duration of ultrasound irradiation for emulsification, and PTX-loaded emulsions with the sizes of approximately 100 nm, 270 nm, and 750 nm were successfully obtained. In

Discussion

Particle size and release property of anti-cancer drug-loaded nanoparticles are considered to be critical determinants of the therapeutic efficacy of nanoparticle-based intraperitoneal chemotherapy. However, there are few reports investigating the substantial effect of these factors on the peritoneal retention and therapeutic efficacy of anti-cancer drug-loaded nanoparticles against MA. Here, we carried out the comparative studies of the biodisposition and therapeutic efficacy of PTX-loaded

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

References (31)

  • Y. Sadzuka et al.

    Effects of administered route on tissue distribution and antitumor activity of polyethyleneglycol-coated liposomes containing adriamycin

    Cancer. Lett.

    (1997)
  • A. Sarfarazi et al.

    Therapeutic delivery to the peritoneal lymphatics: current understanding, potential treatment benefits and future prospects

    Int. J. Pharm.

    (2019)
  • T.D. Yan et al.

    Significance of lymph node metastasis in patients with diffuse malignant peritoneal mesothelioma

    Eur. J. Surg. Oncol.

    (2006)
  • Y. Yoshizawa et al.

    PEG liposomalization of paclitaxel improved its in vivo disposition and anti-tumor efficacy

    Int. J. Pharm.

    (2011)
  • S.M. Abuzar et al.

    Preparation and evaluation of intraperitoneal long-acting oxaliplatin-loaded multi-vesicular liposomal depot for colorectal cancer treatment

    Pharmaceutics

    (2020)
  • Cited by (1)

    • In vivo distribution characteristics and anti-tumor effects of doxorubicin encapsulated in PEG-modified niosomes in solid tumor-bearing mice

      2023, Journal of Drug Delivery Science and Technology
      Citation Excerpt :

      Regarding DOX-encapsulated Tween 60 niosomes, their anti-tumor effects were similar in both PEG and naked niosomes. We previously identified tumor accumulation and the drug release rate of anti-cancer drug-loaded nanoparticles as key factors for their anti-tumor effects [26,27]. Based on these findings, the anti-tumor effects of Tween 60 niosomes being independent of PEG may be attributed to the similar DOX release properties (Fig. 1) and tumor accumulation profiles (Fig. 4) of PEG and naked Tween 60 niosomes.

    1

    Present address: Department of Pharmaceutics, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan.

    2

    Present address: Formulation Development Department, Chugai Pharmaceutical Co., Ltd., 5-5-1 Ukima, Kita-ku, Tokyo 115-8543, Japan.

    View full text