Effects of particle size and release property of paclitaxel-loaded nanoparticles on their peritoneal retention and therapeutic efficacy against mouse malignant ascites
Graphical abstract
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)
- et al.
Lymphatic drug delivery using engineered liposomes and solid lipid nanoparticles
Adv. Drug. Deliv. Rev.
(2011) - et al.
Effect of vesicle size on tissue localization and immunogenicity of liposomal DNA vaccines
Vaccine
(2011) - et al.
High solids emulsions produced by ultrasound as a function of energy density
Ultrason. Sonochem.
(2017) - et al.
Effective light-triggered contents release from helper lipid-incorporated liposomes co-encapsulating gemcitabine and a water-soluble photosensitizer
Int. J. Pharm.
(2018) Intraperitoneal chemotherapy against peritoneal carcinomatosis: current status and future perspective
Surg. Oncol.
(2014)- et al.
Stable paclitaxel formulations in oily contrast medium
J. Control. Release.
(2005) - et al.
Effect of liposome size on peritoneal retention and organ distribution after intraperitoneal injection in mice
Int. J. Pharm.
(2010) - et al.
Development of safe and potent oil-water emulsion of paclitaxel to treat peritoneal dissemination
J. Pharm. Sci.
(2017) - et al.
Nano-chemotherapeutics: maximising lymphatic drug exposure to improve the treatment of lymph-metastatic cancers
J. Control. Release.
(2014) - et al.
Intraperitoneal administration of doxorubicin encapsulating liposomes against peritoneal dissemination
Toxicol. Lett.
(2000)
Effects of administered route on tissue distribution and antitumor activity of polyethyleneglycol-coated liposomes containing adriamycin
Cancer. Lett.
Therapeutic delivery to the peritoneal lymphatics: current understanding, potential treatment benefits and future prospects
Int. J. Pharm.
Significance of lymph node metastasis in patients with diffuse malignant peritoneal mesothelioma
Eur. J. Surg. Oncol.
PEG liposomalization of paclitaxel improved its in vivo disposition and anti-tumor efficacy
Int. J. Pharm.
Preparation and evaluation of intraperitoneal long-acting oxaliplatin-loaded multi-vesicular liposomal depot for colorectal cancer treatment
Pharmaceutics
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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 TechnologyCitation 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.