The use of PVP as a polymeric carrier to improve the plasma half-life of drugs
Introduction
In this post-genome era, the focus on life science research has shifted from genome analyses to genetic and protein function analyses, and recent advances in pharmacoproteomics have been drastic. Due to recent advances in structural genomics, the functions of numerous proteins will be clarified. Thus, the therapeutic application of bioactive proteins, such as newly identified proteins and cytokines, has been highly expected [1], [2], [3], [4]. However, most of these proteins are limited in their clinical application because of unexpectedly low therapeutic effects. The reason for this limitation is that these proteins are immediately decomposed by various proteases in vivo, and are rapidly excreted from the blood circulation. Therefore, frequent administration at an excessively high dose is required to reveal their therapeutic effects in vivo. As a result, homeostasis is destroyed, and unexpected side effects occur. Many cancer chemotherapies utilizing anticancer antibiotics are also limited by such problems. Therefore, in order to overcome the weak points peculiar to many proteins, we attempted to perform chemical modification (bioconjugation) with water-soluble polymers [5], [6], [7], [8], [9]. Bioconjugation with polymeric modifiers improves the plasma clearance and body distribution, resulting in an increase of therapeutic effects and a decrease of side effects. Our results suggest that investigation of the relationship between degree of modification by polymer, molecular size, and specific activity on cytokine bioconjugation may accomplish an increase of therapeutic effect and a decrease of side effects. In addition, our previous study indicates that optimally bioconjugated drugs can achieve well-balanced tissue transport, receptor binding, and plasma clearance, resulting in a selective increase of therapeutic effects.
On the other hand, in order to deliver a bioconjugated drug to targeted tissue, the conjugate must be designed to show desirable pharmacokinetic characteristics, such as plasma clearance and tissue distribution. It is well known that the fate and distribution of the conjugates can be attributed to the physicochemical properties of polymeric modifiers, such as molecular weight, electric charge, and hydrophilic–lipophilic balance [10]. The increase of therapeutic effects of drug bioconjugated with polymeric modifier is attributed to the pharmacokinetics of bioconjugated drug. Therefore, selecting the polymeric modifier by considering the influence of physicochemical characteristics on pharmacokinetics of polymeric modifier is markedly important. As mentioned above, sequential and multiple strategies are needed for optimization of drug therapy based on bioconjugation: (i) optimum selection of polymeric modifier considering the disposition of drugs and objectives such as targeting or controlled release; (ii) bioconjugation based on estimation of characterization, such as molecular size, modification site, degree of modification, and specific activity; and (iii) assessment of therapeutic effect and pharmacokinetics of bioconjugated drug.
In the present study, we first focused on nonionic water-soluble polymers and tried to clarify the pharmacokinetic properties of various polymeric modifiers, which could be modified by the physicochemical property, on mice bearing solid tumors. The polymer formulations used to evaluate these are PEG, polyvinylpyrrolidone (PVP), polyacrylamide (PAAm), polydimethylacrylamide (PDAAm), polyvinyl alcohol (PVA), and dextran. PVP, PAAm, and PDAAm could be functionalized by introduction of various comonomers on radical polymerization. PVA and dextran have many primary OH groups that can be used for bioconjugation on the side chain. Each 125I-labeled water-soluble polymer was injected i.v. into tumor-bearing mice, and plasma clearance in the circulation and tissue distribution were measured. Moreover, we assessed the feasibility of polymeric modifiers for drug delivery based on pharmacokinetic analysis.
Section snippets
Materials
PEGs (average molecular weight: 12,000, 50,000, 70,000, 500,000), acrylamide and N,N′-dimethylacrylamide, sodium pyrosulfate, chloramine T (sodium p-toluenesulfonchloramide trihydrate), thyramine hydrochloride, N,N′-carbonyldiimidazole, dicyclohexylcarbodiimide, N-vinyl-2-pyrrolidone, and N-hydroxysuccinimide were purchased from Wako Pure Chemical Industries, Ltd., Osaka, Japan. Methoxypolyethylene glycol-succinimidyl succinate (average molecular weight: 5000) and dextran (average molecular
Plasma clearance of PEG with various molecular weights
We first compared the plasma clearance of PEGs with various molecular weights (Fig. 1). Elimination profiles of PEGs from the blood circulation varied to a great extent with a change of molecular weight. PEG5000 was most rapidly cleared from the circulation; only about 10% of the injected dose remained 20 min after i.v. administration. PEG12,000 was retained in the blood circulation for a longer period than PEG5000, but 70% of the injected dose was eliminated after 90 min. In addition, similar
Discussion
This study was aimed at clarifying the pharmacokinetic characteristics of various water-soluble polymers in order to design a bioconjugated drug and to optimize drug delivery based on bioconjugation. Additionally, we estimated the biopharmaceutical disposition of polymers in mice bearing solid tumors in consideration of cancer therapy. 125I-labeled polymers showed the pharmacokinetics in mice bearing solid tumors to be the same as in normal mice (data not shown). This fundamental approach
Conclusion
PVP had the longest circulation lifetime among various polymers and its tissue distribution was extremely restricted. PVP-TNF-α showed longer plasma half-life than PEG-TNF-α, and the plasma half-life of PVP-TNF-α was 90-fold higher than that of native TNF-α. These results suggest that PVP is the most suitable polymeric modifier for prolonging the circulation lifetime of a drug and localizing the conjugated drug in blood.
Acknowledgments
This study was supported in part by a Grant-in-Aid for Scientific Research (No. 15680014) from the Ministry of Education, Science and Culture of Japan, and in part by Health Sciences Research Grants for Research on Health Sciences focusing on Drug Innovation from the Japan Health Sciences Foundation (KH63124), and in part by Takeda Science Foundation.
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These authors contributed equally to the work.