Lymphatic Vessels as a Selective Administration Route of Antitumor Agent

Lymphatic Vessels as a Selective Administration Route of

Antitumor Agent

Akira Fujimura

, Masao Onodera

, Nobuo Saito

, Toshihiro Ohta

, Kohichiro Sera

, and Yohichiro Nozoka

Key words. Lymphatic vessel, Drug delivery route, Selective administration route, Tumor, Antitumor agent

Introduction

Enucleation of primary lesion and neck dissection of regional lymph nodes are required in operating on a tumor. As a result, rehabilitation is very diffi- cult following treatment of a tumor, because of the large defect and the side effects. The dissection of regional lymph nodes is required in the operation of mammary cancer and uterine cancer, causing edema of the limb. In other words the quality of life of a patient is adversely affected by current surgical methods. This has been improved by the use of Sentinel navigation surgery, but it is reported that this method is impossible to use in the head and neck region due to the existence of the lymphatic network. We surmised that the quality of life of the patient could be maintained by using the lymph vessels as a drug delivery route after involving the lymphatic network. From our past reports [1–4], we are able to elucidate, to a great extent, the detailed architec- ture of lymphatic vessels in the tongue. However, the network of the lymph nodes in the neck region is very complicated and at present is far from being elucidated. On the other hand, the lymph vessels from every organ connect with the regional lymph nodes as stated in the theory of Sentinel navigation

255

1

First Department of Oral Anatomy,

First Department of Maxillofacial Surgery,

Cyclotron

Research Center, Iwate Medical University, 1-2-27 Chuo-dori, Morioka 020-8505, Japan

surgery and as discovered by research on the lymph vessels. The lymph node dissection which is done currently intercepts the lymph flow from other organs. We propose a method which does not dissect the regional lymph nodes where metastasis is clear. There have been some reports that propose the intratumoral dosage of antitumor agents, but as yet there are no reports regarding use of the lymph vessels as a drug delivery route to metastatic lymph nodes selectively with a high concentration of agent. We injected an antitumor agent into the normal tongue as a preliminary study and confirmed the flow to regional lymph nodes.

Materials and Methods

Mice were injected with 5 and 10 ml of cisplatin (1 mg/ml) (MW: 300.05, Randa, Nippon Kayaku, Japan) to the right side of the normal tongue and taking in the right and left submandibular lymph nodes, blood, liver, and kidney, 0.5, 1 , 3, 6, and 24 h after injection of cisplatin. Samples were dried and prepared by the chemical ashing method using nitric acid, and then analyzed by par- ticle induced X-ray emission. Cisplatin includes platinum which does not exist in generally in organisms, and this free element aids antitumor activity.

Therefore, we can estimate the antitumor activity by measuring the dose of platinum.

Results and Discussion

Platinum was scarcely detected within 24 h in the 5 ml injection group, and only in the submandibular lymph nodes which was the regional lymph node in the 10 ml injection group (Fig. 1). It is clear that the pressure in the tissue triggered absorption by the initial lymph vessels. Cisplatin flowed into both sides of the submandibular lymph nodes and gradually increased propor- tionately with time. It was clear that the cisplatin had a high concentration locally, but a low concentration in the whole body. We believe that by use of this method using the lymphatic vessels as a drug delivery route, the burden on the patient during operation will be reduced and the side effects of the antitumor agent will be inhibited.

256 A. Fujimura et al.

References

1 . Xie X, Fujimura A (2000) Macromolecular clearance in the tongue through lymphatic vessels. Dent J Iwate Med Univ 25:273–282

2 . Fujimura A, Nozaka Y (2002) Analysis of the three-dimensional lymphatic architecture of the periodontal tissue using a new 3D reconstruction method. Microsc Res Tech 56 :60–65

3 . Fujimura A, Seki S, Liao M-Y, et al (2003) Three dimensional architecture of lymphatic vessels in the tongue. Lymphology 36:120–127

4 . Seki S, Fujimura A (2003) Three dimensional changes in lymphatic architecture around VX2 tongue cancer. Dynamics of growth of cancer. Lymphology 36:128–139

5 . Seki S, Fujimura A (2003) Three dimensional changes in lymphatic architecture around VX2 tongue cancer. Dynamic changes after administration of antiangiogenic agent.

Lymphology 36:199–208

Lymphatic Vessels as Selective Administration Route 257

: left submandibular lymph node

1 2 3 4

0.5 1 3 6 24 (hours)

(mg/mg)

: right submandibular lymph node (injection side)

: other organs (blood, liver, kidney)

Fig. 1. Time course analysis of platinum by particle induced X-ray emission. Platinum

increases throughout the time course. Regarding quantity of platinum, the submandibular

lymph node of the injection side contains less than half that of the one on the opposite

side. Platinum could not be detected in other organs