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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 ...

The amino group of doxorubicin (DXR) was found to be bound to the carboxyl group of carboxymethylpullulan (CMPul) either directly or through tetrapeptide spacers, including Gly-Gly-Phe-Gly, Gly-Phe-Gly-Gly and Gly-Gly-Gly-Gly. These conjugates had DXR contents of 6.1-7.1%, with the degree of substitution of carboxymethyl groups being 0.6 per sugar moiety. These conjugates associate in phosphate-buffered saline (PBS) (pH 7.4), forming micelles with hydrophobic DXR inside and hydrophilic CMPul on the outside. The amounts of DXR released from the conjugates in the presence of rat liver lysosomal enzymes were determined by HPLC. The rate of the drug release differed among the conjugates tested. CMPul-DXR conjugate bound through Gly-Gly-Phe-Gly released 35% of its DXR over 24 h. On the other hand, CMPul-DXR conjugate without spacer released no free DXR. The antitumor effect of each conjugate in rats bearing Walker 256 was studied by monitoring the tumor weights after a single intravenous injection. Compared with DXR, CMPul-DXR conjugates bound through Gly-Gly-Phe-Gly and Gly-Phe-Gly-Gly spacers significantly suppressed the tumor growth, while CMPul-DXR conjugate bound through Gly-Gly-Gly-Gly showed less antitumor effect than DXR. CMPul-DXR conjugate bound through Gly-Gly-Gly-Gly showed less antitumor effect than DXR. CMPul-DXR conjugate without spacer showed no in vivo antitumor effect even at a dose equivalent to as much as 20 mg/kg of DXR.

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To extend the utility of a renal targeting system using carbohydrate derivatives, we investigated the in vivo tissue distribution in rats of arginine-vasopressin (AVP) derivatives modified at the phenolic hydroxy group of tyrosine by linking it to some sugars, namely D-glucose, D-galactose, D-mannose and L-fucose, via an octamethylene group. The glycosyl and mannosyl derivatives of AVP exhibit renal-selective distribution in vivo. In addition, the glucosyl and mannosyl derivatives exhibited specific binding to the kidney microsomal fraction in vitro. Modification with D-glucose or D-mannose at the tyrosine side chain is a suitable methodology for renal targeting, as well as at N-terminal amine.

To evaluate the effect of introducing a saccharide moiety to poly(amino acids) on tissue distribution, several glycoconjugates of epsilon-(2-methoxyethoxyacetyl)-poly(L-lysine) of three molecular weights were synthesized using an octylene spacer between the sugar and polymer chain. Methoxyethoxyacetylation of the epsilon-amino group of the lysine unit in poly(L-lysine) was useful for avoiding nonspecific distribution to many tissues as the result of cationic charges. The tissue-targeting ability of each saccharide moiety was considered as the actual amount changed in each tissue caused by saccharide modification. Galactose terminated saccharides such as galactose, lactose and N-acetylgalactosamine accumulated exclusively in the liver, probably by the hepatic receptor. These conjugates could therefore be good carriers for a drug delivery system to the liver. On the other hand, the mannosyl and fucosyl conjugates were preferentially delivered to the reticuloendothelial systems such as those in the liver, spleen and bone marrow. In particular, fucosyl conjugates accumulated more in the bone marrow than in the spleen. Xylosyl conjugates accumulated mostly in the liver and lung. Generally, the accumulated amount in the target tissue increased with increasing molecular weight and an increased number of saccharides on one molecule of polymer.

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