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structure and retention of the loaded drugs as well ' .

Figure J. Time profiles of "C-labeled Dox in blood (A) or in the tumor (C-26) (B) in CDF| mice after i.v. drug administration ( A;free Dox; OPEG-PAspiDox) micelle Rui I: •;Run 2). Dose was either 10 nig/kg for free Dot and 10 mg of physically entrapped Dox (including a dimer of Dox) per kg for PEG-PAsp(Dox; micelle. PEG-PAsp(Dox) micelle Rui 1 and 2 were prepared at the ratio of chemically conjugated to physically entrapped Dox of 1.0 to 0.39 and 1.0 to 0.98. respectively. (Reprinted with permission from Ref. (8). Copyright 1999 Taylor & Francis.)

Figure J. Time profiles of "C-labeled Dox in blood (A) or in the tumor (C-26) (B) in CDF| mice after i.v. drug administration ( A;free Dox; OPEG-PAspiDox) micelle Rui I: •;Run 2). Dose was either 10 nig/kg for free Dot and 10 mg of physically entrapped Dox (including a dimer of Dox) per kg for PEG-PAsp(Dox; micelle. PEG-PAsp(Dox) micelle Rui 1 and 2 were prepared at the ratio of chemically conjugated to physically entrapped Dox of 1.0 to 0.39 and 1.0 to 0.98. respectively. (Reprinted with permission from Ref. (8). Copyright 1999 Taylor & Francis.)

In biodistribution assay where only the physically entrapped Dox in the micelles was radio-labeled with 14C, PEG-PAsp(Dox) micelles showed remarkably prolonged blood circulation (24.6 % of injected dose was found at 24 h), while free Dox disappeared very quickly from the circulation (1.6 % of injected dose at 15 min) (Fig. 3 A) 8. The plasma-to-blood partitioning ratio demonstrated that PEG-PAsp(Dox) micelles existed predominantly in the plasma fraction during the circulation (up to 48 h) while free Dox distributed to the blood cells. As for tissue accumulation, there was no notable difference for accumulation in the liver, spleen, kidney and heart between PEG-PAsp(Dox) micelles and free Dox 8. In contrast to normal organs, PEG-PAsp(Dox) micelles accumulated effectively in the subcutaneously inoculated tumor (murine colon adenocarcinoma (C-26)) over 24 h, and eventually exhibited 7.4-fold higher tumor accumulation than free Dox at 24 h (Fig. 3 B) 8. Such effective tumor accumulation of PEG-PAsp(Dox) micelles is most probably due to the EPR effect described in Section 2.2. of this chapter and elsewhere in this book. Consequently, PEG-PAsp(Dox) micelles showed higher tumor-to-normal tissue accumulation ratios (i.e., targeting efficiency) than free Dox (Table 1), suggesting improved therapeutic indices of the micellar formulation. Indeed, PEG-PAsp(Dox) micelles showed such significant in vivo antitumor activity as to lead to a complete tumor regression against C-26 8. It is worth noting that longer blood circulation, higher tumor accumulation and slower in vivo drug release were observed for the micelles with a higher loading amount of physically entrapped Dox (Fig. 3 and Table 1) 8, suggesting that the micellar stability and drug release rate in vivo can be controlled by the proportion of chemically conjugated Dox to the PAsp segments as well as loading amount of physically entrapped Dox and dimer of Dox. Therefore, it may be feasible to design the polymeric micelle formulation with preferable

Table 1. Accumulation ratios between tumor (C-26) and normal organs (Dose: 10 mg/kg for free Dox and 10 mg of physically entrapped Dox per kg for PEG-PAsp(Dox) micelle). (Reprinted with permission from Ref. [8]. Copyright 1999 Taylor &. Francis.)
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