Elsevier BV Acta Medica Okayama 1773-2247 106 2025 EGF-induced P-gp expression in tumor vasculature contributes to therapeutic resistance to doxorubicin-PEG-liposomes in mice bearing doxorubicin-resistant B16-BL6 tumors 106690 EN Masato Maruyama Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University Tomoki Ueda Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University Yusuke Ienaka Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University Haruka Tojo Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University Kenji Hyodo Eisai Co., Ltd. Ken-ichi Ogawara Laboratory of Pharmaceutics, Kobe Pharmaceutical University Kazutaka Higaki Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University We previously indicated that doxorubicin (DOX)-loaded polyethylene glycol (PEG)-modified liposomes (DOX-PEG-liposomes) were therapeutically effective in mice bearing DOX-resistant colon-26 (C26/DOX) tumors, and the efficacy was comparable in mice bearing DOX-sensitive C26 tumors. However, in the current study, DOX-PEG-liposomes exerted no therapeutic activity in DOX-resistant B16-BL6 melanoma (B16/DOX)-bearing mice, although they significantly suppressed DOX-sensitive B16 tumor growth in mice. Although we previously reported that the anti-tumor effects in C26/DOX-bearing mice were derived from the cytotoxic effects of DOX on vascular endothelial cells (VECs) in tumors, the B16/DOX tumor vasculature was not substantially damaged after administration of DOX-PEG-liposomes. In B16/DOX tumors, P-gp expression was significantly induced in the VECs, but not in the C26/DOX tumors, indicating that the high expression of P-gp in the tumor vasculature would be responsible for the lack of therapeutic effect of DOX-PEG-liposomes in B16/DOX-bearing mice. Epidermal growth factor (EGF), a possible induction factor for P-gp expression, was highly expressed in B16/DOX cells and tumor tissues, and significantly induced P-gp expression in human umbilical vein endothelial cells (HUVEC). The EGF receptor (EGFR) was also highly expressed in B16/DOX tumor VECs, suggesting that the activation of EGF/EGFR signaling may induce P-gp expression in VECs in B16/DOX tumors. No potential conflict of interest relevant to this article was reported.

Elsevier BV Acta Medica Okayama 0939-6411 209 2025 Repeated sequential administration of pegylated emulsion of SU5416 and liposomal paclitaxel enhances anti-tumor effect in 4T1 breast cancer-bearing mice 114663 EN Masato Maruyama Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University Reiya Torii Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University Hazuki Matsui Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University Hiroki Hayashi Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University Ken-ichi Ogawara Laboratory of Pharmaceutics, Kobe Pharmaceutical University Kazutaka Higaki Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University To improve vascular normalization strategy for intractable triple-negative breast cancer 4T1, we examined the anti-tumor effects of repeated sequential administration of polyethylene glycol (PEG)-modified emulsion of SU5416 (PE-SU5416), a vascular endothelial growth factor (VEGF) receptor-2 kinase inhibitor, and PEG-modified liposomal paclitaxel (PL-PTX) in mice bearing 4T1 cells. Three sequential administrations (Seq�~3) of PE-SU5416 and PL-PTX exhibited significantly higher anti-tumor activity than a single sequential administration (Seq�~1). The tumor vasculatures were structurally normalized until after two PE-SU5416 (PE-SU5416�~2) or sequential (Seq�~2) administrations, while the improvement in vascular function, such as oxygen supply, blood flow, and PEG-liposomal distribution, was evident until after three administrations of PE-SU5416 (PE-SU5416�~3) and Seq�~3. Although some discrepancies between the structural and functional improvement in tumor vasculatures were observed after PE-SU5416�~3 and Seq�~3, cancer-associated fibroblasts (CAFs) and collagen levels were significantly reduced after PE-SU5416�~2, PE-SU5416�~3, Seq�~2, and Seq�~3, suggesting that a possible decrease in interstitial fluid pressure due to the reduction in CAFs and collagen would have compensated for vascular function. Furthermore, PE-SU5416�~2, PE-SU5416�~3, Seq�~2, and Seq�~3 significantly decreased tumor growth factor-ƒÀ (TGF-ƒÀ), an activator of CAFs, in tumor tissues, suggesting that the reduction in TGF-ƒÀ levels by PE-SU5416 suppresses CAF activation. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 1999-4923 15 1 2022 Formation of a Stable Co-Amorphous System for a Brick Dust Molecule by Utilizing Sodium Taurocholate with High Glass Transition Temperature 84 EN Shohei Aikawa Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University Hironori Tanaka Formulation Research Department, Formulation R&D Laboratory, Shionogi & Co., Ltd. Hiroshi Ueda Bioanalytical, Analysis and Evaluation Laboratory, Shionogi & Co., Ltd. Masato Maruyama Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University Kazutaka Higaki Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University Brick dust molecules are usually poorly soluble in water and lipoidal components, making it difficult to formulate them in dosage forms that provide efficient pharmacological effects. A co-amorphous system is an effective strategy to resolve these issues. However, their glass transition temperatures (Tg) are relatively lower than those of polymeric amorphous solid dispersions, suggesting the instability of the co-amorphous system. This study aimed to formulate a stable co-amorphous system for brick dust molecules by utilizing sodium taurocholate (NaTC) with a higher Tg. A novel neuropeptide Y-5 receptor antagonist (AntiY(5)R) and NaTC with Tg of 155 degrees C were used as the brick dust model and coformer, respectively. Ball milling formed a co-amorphous system for AntiY(5)R and NaTC (AntiY(5)R-NaTC) at various molar ratios. Deviation from the theoretical Tg value and peak shifts in Fourier-transform infrared spectroscopy indicated intermolecular interactions between AntiY(5)R and NaTC. AntiY(5)R-NaTC at equal molar ratios resulting in an 8.5-fold increase in AntiY(5)R solubility over its crystalline form. The co-amorphous system remained amorphous for 1 month at 25 degrees C and 40 degrees C. These results suggest that the co-amorphous system formed by utilizing NaTC as a coformer could stably maintain the amorphous state and enhance the solubility of brick dust molecules. No potential conflict of interest relevant to this article was reported.

Acta Medica Okayama 353 1-2 2008 Albumin-conjugated PEG liposome enhances tumor distribution of liposomal doxorubicin in rats 28 34 EN Jun-ichi Yokoe Shiho Sakuragi Kayoko Yamamoto Takuya Teragaki Ken-ichi Ogawara Kazutaka Higaki Naohisa Katayama Toshiya Kai Makoto Sato Toshikiro Kimura <p>To evaluate the effect of coupling of recombinant human serum albumin (rHSA) onto the surface of poly(ethylene glycol)-modified liposorne (PEG liposome) on the in vivo disposition characteristics of liposomal doxorubicin (DXR), the pharmacokinetics and tissue distribution of DXR were evaluated after intravenous administration of rHSA-modified PEG (rHSA/PEG) liposomal DXR into tumor-bearing rats. rHSA/PEG liposome prepared using a hetero-bifunctional cross-linker, N- succinimidyl 3-(2-pyridyldithio) propionate (SPDP), efficiently encapsulated DXR (over 95%). rHSA/PEG liposomal DXR showed longer blood-circulating property than PEG liposornal DXR and the hepatic and splenic clearances of rHSA/PEG liposornal DXR were significantly smaller than those of PEG liposomal DXR. It was also demonstrated that the disposition of DXR to the heart, one of the organs for DXR-related side-effects, was significantly smaller than free DXR. Furthermore, the tumor accumulation of rHSA/PEG liposomal DXR was significantly larger than that of PEG liposomal DXR. The &#34;therapeutic index&#34;, a criterion for therapeutic outcome, for rHSA/PEG fiposornal DXR was significantly higher than PEG liposomal DXR. These results clearly indicate that rHSA-conjugation onto the surface of PEG liposome would be a useful approach to increase the effectiveness and safety of PEG liposomal DXR.</p> No potential conflict of interest relevant to this article was reported.