Tailor-making of protein drugs by polymer conjugation for tumor targeting: A brief review on smancs

Augmentation of tumour delivery of macromolecular drugs with reduced bone marrow delivery by elevating blood pressure

“…We have also found another phenomenon that little lymphatic clearance of lipids (Konno et al, 1984a,b;Iwai et al, 1984;Maeda et al, 1984;Iwai et al, 1987) and macromolecules Matsumura & Maeda, 1986;Maeda & Matsumura, 1989;Maeda, 1991) from solid tumours takes place.…”

“…On the basis of this principle, AT-IL-induced hypertensive chemotherapy has been initiated in Japan (Tables II and III). In general, macromolecules and lipids in the interstitial space are known to be recovered mainly by the lymphatics in normal tissues (Courtice, 1963), but they seemed unlikely to be cleared from tumour tissue effectively Iwai et al, 1987;Maeda et al, 1984;Matsumura & Maeda, 1986). If the accumulated macromolecules in tumour could be drained by the operating lymphatics there would be no accumulation of the macromolecular drugs as in normal tissue.…”

“…Thus, it would be useful to study the influence of AT-IT-induced hypertension on the distribution of macromolecules in tumour and normal tissues. SMANCS, styrene-maleic acid copolymer-conjugated neocarzinostatin (Maeda et al, 1979a,b;Takeshita et al, 1982;Maeda et al, 1984;Maeda et al, 1985) (Khaw et al, 1980;Hnatowich et al, 1982;Matsumura & Maeda, 1986 Evaluation of toxicities SMANCS at a dose giving 50% lethality (LD50) (2 mg kg-') was injected i.v. via the tail vein of normal rats without tumour under hypertensive or normotensive conditions.…”

“…If this objective could be achieved, undesirable toxicities of a drug to normal tissues, such as the bone marrow, will be reduced and therapeutic efficacy will improve. We have developed an effective way of achieving highly tumouritropic delivery of drugs by using macromolecules and taking advantage of the unique characteristics of the blood and lymphatic vasculatures of tumour tissue (Maeda et al, 1979a,b;Takeshita et al, 1982;Maeda et al, 1984;Matsumura & Maeda, 1986;Maeda & Matsumura, 1989;Maeda, 1991;Maeda et al, 1992). Namely, most solid tumours possess vasculature that is densely and irregularly developed, and hyperpermeable to macromolecules; however, they usually lack functioning lymphatics, which leads to selective deposition of macromolecules in tumour tissues.…”

Trends in Biomedical Nanotechnology

“…There is a huge interest in employing nanotechnology for cancer drug delivery. The interest in cancer drug delivery stems from the fact that the nanoparticles passively target tumors by a process called enhanced permeability and retention (EPR) effect, as elucidated by Maeda and coworkers [4][5][6]. It occurs because the tight junctions between endothelial cells of microvessels measure around 2 nm (6 nm in kidney, liver, and spleen), whereas the pore size of tumor microvessels varies from 100 to 1200 nm.…”