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Synthesis and therapeutic effect of styrene-maleic acid copolymer-conjugated pirarubicin.

Tsukigawa K, Liao L, Nakamura H, Fang J, Greish K, Otagiri M, Maeda H - Cancer Sci. (2015)

Bottom Line: The SMA-THP conjugate also formed micelles and showed albumin binding capacity in aqueous solution, which suggested that this conjugate behaved as a macromolecule during blood circulation.Consequently, SMA-THP conjugate showed significantly prolonged circulation time compared to free THP and high tumor-targeting efficiency by the enhanced permeability and retention (EPR) effect.These findings suggest the potential of SMA-THP conjugate as a highly favorable candidate for anticancer nanomedicine with good stability and tumor-targeting properties in vivo.

View Article: PubMed Central - PubMed

Affiliation: Institute for Drug Delivery Science, Sojo University, Kumamoto, Japan; Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan.

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Related in: MedlinePlus

Pharmacokinetics of free pirarubicin (THP) and styrene‚Äďmaleic acid copolymer (SMA)-conjugated THP (SMA-THP conjugate) after i.v. injection. (a) Blood levels of both drugs after injection in an S-180 tumor model. (b, c) Tissue distribution of free THP and/or SMA-THP conjugate after i.v. injection in an S-180 tumor model. (d) Relative tissue distribution at 24¬†h after i.v. injection of free THP and SMA-THP conjugate in healthy SD rats. (e) Comparison of tissue distribution of SMA-THP conjugate at 24 and 72¬†h after i.v. injection in SD rats. Values are mean¬†¬Ī¬†SEM (n¬†=¬†3). *P¬†<¬†0.05.
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fig04: Pharmacokinetics of free pirarubicin (THP) and styrene‚Äďmaleic acid copolymer (SMA)-conjugated THP (SMA-THP conjugate) after i.v. injection. (a) Blood levels of both drugs after injection in an S-180 tumor model. (b, c) Tissue distribution of free THP and/or SMA-THP conjugate after i.v. injection in an S-180 tumor model. (d) Relative tissue distribution at 24¬†h after i.v. injection of free THP and SMA-THP conjugate in healthy SD rats. (e) Comparison of tissue distribution of SMA-THP conjugate at 24 and 72¬†h after i.v. injection in SD rats. Values are mean¬†¬Ī¬†SEM (n¬†=¬†3). *P¬†<¬†0.05.

Mentions: As shown in Figure4(a), free THP was cleared rapidly from blood circulation after i.v. injection, whereas SMA-THP conjugate remained high in blood circulation for a much longer time, with a 24.5-fold higher concentration curve than free THP. At 24 h after i.v. injection (Fig.4b), free THP showed the highest concentration in spleen, followed by liver; the accumulation in tumor was very low, at approximately 13% of that in spleen. Accumulation of SMA-THP conjugate was highest in liver, while drug levels in tumor were higher than most other normal tissues. The high accumulation in liver is similar to previous SMA-conjugated drugs (e.g. SMANCS) as well as other macromolecular drugs, mostly through the reticuloendothelial system (e.g. macrophages).5,18 In addition, high accumulation of SMA-THP conjugate in kidney was also observed, which is probably due to the disintegrated chemical unit of SMA-THP conjugate from micelles whose molecular size (approximately 2200) is smaller than the renal threshold (40 kDa).


Synthesis and therapeutic effect of styrene-maleic acid copolymer-conjugated pirarubicin.

Tsukigawa K, Liao L, Nakamura H, Fang J, Greish K, Otagiri M, Maeda H - Cancer Sci. (2015)

Pharmacokinetics of free pirarubicin (THP) and styrene‚Äďmaleic acid copolymer (SMA)-conjugated THP (SMA-THP conjugate) after i.v. injection. (a) Blood levels of both drugs after injection in an S-180 tumor model. (b, c) Tissue distribution of free THP and/or SMA-THP conjugate after i.v. injection in an S-180 tumor model. (d) Relative tissue distribution at 24¬†h after i.v. injection of free THP and SMA-THP conjugate in healthy SD rats. (e) Comparison of tissue distribution of SMA-THP conjugate at 24 and 72¬†h after i.v. injection in SD rats. Values are mean¬†¬Ī¬†SEM (n¬†=¬†3). *P¬†<¬†0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4376435&req=5

fig04: Pharmacokinetics of free pirarubicin (THP) and styrene‚Äďmaleic acid copolymer (SMA)-conjugated THP (SMA-THP conjugate) after i.v. injection. (a) Blood levels of both drugs after injection in an S-180 tumor model. (b, c) Tissue distribution of free THP and/or SMA-THP conjugate after i.v. injection in an S-180 tumor model. (d) Relative tissue distribution at 24¬†h after i.v. injection of free THP and SMA-THP conjugate in healthy SD rats. (e) Comparison of tissue distribution of SMA-THP conjugate at 24 and 72¬†h after i.v. injection in SD rats. Values are mean¬†¬Ī¬†SEM (n¬†=¬†3). *P¬†<¬†0.05.
Mentions: As shown in Figure4(a), free THP was cleared rapidly from blood circulation after i.v. injection, whereas SMA-THP conjugate remained high in blood circulation for a much longer time, with a 24.5-fold higher concentration curve than free THP. At 24 h after i.v. injection (Fig.4b), free THP showed the highest concentration in spleen, followed by liver; the accumulation in tumor was very low, at approximately 13% of that in spleen. Accumulation of SMA-THP conjugate was highest in liver, while drug levels in tumor were higher than most other normal tissues. The high accumulation in liver is similar to previous SMA-conjugated drugs (e.g. SMANCS) as well as other macromolecular drugs, mostly through the reticuloendothelial system (e.g. macrophages).5,18 In addition, high accumulation of SMA-THP conjugate in kidney was also observed, which is probably due to the disintegrated chemical unit of SMA-THP conjugate from micelles whose molecular size (approximately 2200) is smaller than the renal threshold (40 kDa).

Bottom Line: The SMA-THP conjugate also formed micelles and showed albumin binding capacity in aqueous solution, which suggested that this conjugate behaved as a macromolecule during blood circulation.Consequently, SMA-THP conjugate showed significantly prolonged circulation time compared to free THP and high tumor-targeting efficiency by the enhanced permeability and retention (EPR) effect.These findings suggest the potential of SMA-THP conjugate as a highly favorable candidate for anticancer nanomedicine with good stability and tumor-targeting properties in vivo.

View Article: PubMed Central - PubMed

Affiliation: Institute for Drug Delivery Science, Sojo University, Kumamoto, Japan; Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan.

Show MeSH
Related in: MedlinePlus