Many macromolecular drug conjugates have been developed for the purpose of optimizing the pharmacokinetic profile of anti-tumor drugs. The drugs are chemically coupled to these macromolecules, enabling them to be transported through the bloodstream and to be delivered to tumor tissues without being metabolized. Macromolecules are well known to accumulate in the tumor tissue through a mechanism known as the "enhanced permeability and retention (EPR) effect."1)The use of macromolecules for the delivery of doxorubicin (DXR) [2][3][4] to tumors was investigated in a previous study 5) and is believed to enhance efficacy and reduce systemic side effects. 6) Recently, the N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-DXR conjugate, called PK1, has entered clinical development in the UK 7,8) and its Phase 1 results 9) showed that by conjugating the drug with a macromolecule, its distribution properties could be altered depending on the properties of the carrier macromolecules. 10,11) Various macromolecules, such as immunoglobulins, 12) albumin, 13) polyaminoacids, [14][15][16][17][18][19] synthetic polymers, 20,21) and polysaccharides, [22][23][24][25] have traditionally been used as drug carriers; however, this approach does not always produce the desired results in vivo since the distribution characteristics of these drug carriers has so far not been characterized and, therefore, is not well known. In particular, there is not enough information about the distribution properties and physicochemical characteristics of polysaccharides to select suitable drug carriers for tumor targeting.The present study focused on the relationship between the tissue distribution of macromolecular carriers derived from naturally occurring polysaccharides, and their physicochemical characteristics, namely, molecular weight (MW) and electric charge, or as it is often called, degree of substitution (DS). These have been reported by Nishikawa et al. 26) to play an important role in tissue distribution. The macromolecules selected as drug carriers were polysaccharide derivatives: CMDex, CMMG, CMCh, HA, and DSH. The choice was based on the reasoning that: (a) these polysaccharide derivatives are potentially biocompatible; (b) they contain a large number of carboxyl groups for drug attachment and provide sufficient carrying capacity for the drug; and (c) the resulting drug conjugates promised to be water-soluble. Having previously investigated some of the characteristics of D-manno-Dglucan (MG) and its derivatives, 27,28) we decided to decrease their anticoagulant activity by selectively N-desulfating and then N-acetylating 29) heparin. To test the relationship between the molecular weight and anionic charge (MW and DS of CM groups) of these polysaccharide carriers to their tissue distribution, carrier-DXR conjugates were prepared by binding their components directly or via a GGFG spacer. Their respective antitumor effects were then tested in vivo on Walker 256 carcinosarcomabearing rats. It was shown that polymeric modification of DXR ...
