Selective targeting of anti-cancer drug and simultaneous image enhancement in solid tumors by arterially administered lipid contrast medium

Abstract

Twenty‐four patients with various solid tumors including metastatic liver cancer and cancer of the lung, gallbladder, and pancreas were treated with a lipophilic macromolecular drug, copoly(styrene‐maleic acid) conjugated neocarzinostatin (SMANCS). The drug was dissolved in a lipid contrast medium Lipiodol and administered by catheterizing the respective feeding arteries under x‐ray monitoring. The advantages of this therapy include: (1) selective deposition of Lipiodol with the anti‐cancer drug in the target tumor, (2) a pronounced and long‐lasting anti‐cancer effect, (3) enhanced visulization of the tumor on x‐ray examinations for a prolonged period which also facilitated the long‐term follow‐up, (4) semiquantitative evaluation of the dosage regimen by x‐ray examination before further administration, (5) general applicability due to procedural simplicity, and (6) little side effect. Since the amount of Lipiodol and SMANCS used per administration for a patient (1.0–5.0 ml; 1.0–5.0 mg) was far less that the anticipated toxicity (LD50 of Lipiodol = 95 ml/60 kg, dog, intravenously; and that of SMANCS = 3.4 mg/kg, mouse, IV), no deleterious effects to such critical organs as the brain, heart, lung, liver, or kidneys were observed upon radiologic and general clinical examination.

In vitro and in vivo evaluation of tumor targeting styrene‐maleic acid copolymer‐pirarubicin micelles: Survival improvement and inhibition of liver metastases

“…(1,3,(6)(7)(8)(9)(10)(11)(12) We have previously characterized tumor vessels as dilated and tortuous with irregular diameters and aberrant branching as well as leakage of polymeric resin (6)(7)(8)(9) and loose endothelial cell-cell gap junctions as large as 600-800 nm. (3,10,11) In addition, we and others identified excessive production of mediators of vascular permeability including bradykinin, nitric oxide, prostaglandins, and vascular endothelial growth factor (VEGF) that also contribute to hyperpermeability of tumor vessels as well as host vessels at the periphery of tumors.(12-16) These differences were first reported by Maeda et al( [1][2][3][16][17][18][19][20] Tumor-associated lymphatic vessels also show irregularities in structure and some tumors show a complete lack of lymphatics, and therefore drainage has been found to be impaired in tumors.In addition to tumor targeting, macromolecular drugs are known to have increased plasma circulation times; the half-life in circulation and intratumoral concentrations can be as high as 20-to 200-fold (2,9,(17)(18)(19)(20)(21) compared to low MW free drugs. In the clinical setting, tumor-selective targeting using macromolecules has been observed with gallium scintigraphy, where radioactive gallium binds to tumor-associated transferrin (90 kDa), and SMANCS (polystyrene-co-maleic acid conjugated neocarzinostatin) ⁄ Lipiodol, with the high electron density of lipiodol, both exclusively accumulate in tumors.…”

Hepatic arterial chemotherapy for metastatic colorectal carcinoma

“…Furthermore, it would appear that SMANCS has broadspectrum activity, being effective against a number of different solid tumours. Konno et al (1984) reported their experience of treating 24 patients with a variety of solid tumours, 11 of whom had colorectal hepatic metastases. HAI with SMANCS/Lipiodol resulted in tumour response in ten of these patients, four of whom underwent subsequent resection of their residual tumour.…”

Implantation treatment method of slow release anticancer doxorubicin containing hydroxyapatite (DOX-HAP) complex. A basic study of a new treatment for hepatic cancer

“…However, there is a demand for a treatment which has a less liver -and general toxicity or systemic side effect, in addition to the local anticancer effect. Targeting therapies, using a microcapsule, fat, and lipiodol methods have recently improved (Audisio et al, 1990;Gregoriadis, 1977;Kato, 1983;Kato et al, 1980Kato et al, , 1984Konno et al, 1983Konno et al, , 1984Widder et al, 1979). These methods were made possible by primary targeting through the nutrient artery of the tumour and complete secondary targeting by adding the embolisation effect.…”

“…Anticancer drugs, however, have a very low therapeutic index because of their strong cytotoxicity and the large dosage required to produce the desired effect. To overcome these problems, targeting chemotherapy with drug-carrier complexes was invented, using a microcapsule (Kato et al, 1980), fat (Takahashi et al, 1973), carbon (Hagiwara et al, 1987), dextran (Hashida et al, 1981), and lipiodol (Konno et al, 1983(Konno et al, , 1984.…”