start-ver=1.4 cd-journal=joma no-vol=106 cd-vols= no-issue= article-no= start-page=106690 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202504 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=EGF-induced P-gp expression in tumor vasculature contributes to therapeutic resistance to doxorubicin-PEG-liposomes in mice bearing doxorubicin-resistant B16-BL6 tumors en-subtitle= kn-subtitle= en-abstract= kn-abstract=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. en-copyright= kn-copyright= en-aut-name=MaruyamaMasato en-aut-sei=Maruyama en-aut-mei=Masato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=UedaTomoki en-aut-sei=Ueda en-aut-mei=Tomoki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=IenakaYusuke en-aut-sei=Ienaka en-aut-mei=Yusuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TojoHaruka en-aut-sei=Tojo en-aut-mei=Haruka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HyodoKenji en-aut-sei=Hyodo en-aut-mei=Kenji kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=OgawaraKen-ichi en-aut-sei=Ogawara en-aut-mei=Ken-ichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=HigakiKazutaka en-aut-sei=Higaki en-aut-mei=Kazutaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= affil-num=1 en-affil=Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Eisai Co., Ltd. kn-affil= affil-num=6 en-affil=Laboratory of Pharmaceutics, Kobe Pharmaceutical University kn-affil= affil-num=7 en-affil=Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=Drug resistance kn-keyword=Drug resistance en-keyword=P-glycoprotein kn-keyword=P-glycoprotein en-keyword=Liposome kn-keyword=Liposome en-keyword=Tumor vascular endothelial cells kn-keyword=Tumor vascular endothelial cells en-keyword=Melanoma kn-keyword=Melanoma END start-ver=1.4 cd-journal=joma no-vol=209 cd-vols= no-issue= article-no= start-page=114663 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2025 dt-pub=202504 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Repeated sequential administration of pegylated emulsion of SU5416 and liposomal paclitaxel enhances anti-tumor effect in 4T1 breast cancer-bearing mice en-subtitle= kn-subtitle= en-abstract= kn-abstract=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. en-copyright= kn-copyright= en-aut-name=MaruyamaMasato en-aut-sei=Maruyama en-aut-mei=Masato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ToriiReiya en-aut-sei=Torii en-aut-mei=Reiya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=MatsuiHazuki en-aut-sei=Matsui en-aut-mei=Hazuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=HayashiHiroki en-aut-sei=Hayashi en-aut-mei=Hiroki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=OgawaraKen-ichi en-aut-sei=Ogawara en-aut-mei=Ken-ichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=HigakiKazutaka en-aut-sei=Higaki en-aut-mei=Kazutaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University kn-affil= affil-num=3 en-affil=Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University kn-affil= affil-num=4 en-affil=Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Laboratory of Pharmaceutics, Kobe Pharmaceutical University kn-affil= affil-num=6 en-affil=Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=Drug delivery kn-keyword=Drug delivery en-keyword=Vascular normalization kn-keyword=Vascular normalization en-keyword=Breast cancer kn-keyword=Breast cancer en-keyword=Liposome kn-keyword=Liposome en-keyword=Cancer-associated fibroblast kn-keyword=Cancer-associated fibroblast END start-ver=1.4 cd-journal=joma no-vol=15 cd-vols= no-issue=1 article-no= start-page=84 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2022 dt-pub=20221227 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Formation of a Stable Co-Amorphous System for a Brick Dust Molecule by Utilizing Sodium Taurocholate with High Glass Transition Temperature en-subtitle= kn-subtitle= en-abstract= kn-abstract=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. en-copyright= kn-copyright= en-aut-name=AikawaShohei en-aut-sei=Aikawa en-aut-mei=Shohei kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=TanakaHironori en-aut-sei=Tanaka en-aut-mei=Hironori kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=UedaHiroshi en-aut-sei=Ueda en-aut-mei=Hiroshi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MaruyamaMasato en-aut-sei=Maruyama en-aut-mei=Masato kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HigakiKazutaka en-aut-sei=Higaki en-aut-mei=Kazutaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil=Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University kn-affil= affil-num=2 en-affil=Formulation Research Department, Formulation R&D Laboratory, Shionogi & Co., Ltd. kn-affil= affil-num=3 en-affil=Bioanalytical, Analysis and Evaluation Laboratory, Shionogi & Co., Ltd. kn-affil= affil-num=4 en-affil=Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University kn-affil= affil-num=5 en-affil=Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University kn-affil= en-keyword=amorphous kn-keyword=amorphous en-keyword=co-amorphous kn-keyword=co-amorphous en-keyword=crystallization kn-keyword=crystallization en-keyword=sodium taurocholate kn-keyword=sodium taurocholate en-keyword=glass transition temperature kn-keyword=glass transition temperature en-keyword=intermolecular interaction kn-keyword=intermolecular interaction en-keyword=dissolution testing kn-keyword=dissolution testing END start-ver=1.4 cd-journal=joma no-vol=353 cd-vols= no-issue=1-2 article-no= start-page=28 end-page=34 dt-received= dt-revised= dt-accepted= dt-pub-year=2008 dt-pub=20080529 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Albumin-conjugated PEG liposome enhances tumor distribution of liposomal doxorubicin in rats en-subtitle= kn-subtitle= en-abstract= kn-abstract=

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 "therapeutic index", 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.

en-copyright= kn-copyright= en-aut-name=YokoeJun-ichi en-aut-sei=Yokoe en-aut-mei=Jun-ichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=SakuragiShiho en-aut-sei=Sakuragi en-aut-mei=Shiho kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=YamamotoKayoko en-aut-sei=Yamamoto en-aut-mei=Kayoko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=TeragakiTakuya en-aut-sei=Teragaki en-aut-mei=Takuya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=OgawaraKen-ichi en-aut-sei=Ogawara en-aut-mei=Ken-ichi kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=HigakiKazutaka en-aut-sei=Higaki en-aut-mei=Kazutaka kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KatayamaNaohisa en-aut-sei=Katayama en-aut-mei=Naohisa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KaiToshiya en-aut-sei=Kai en-aut-mei=Toshiya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=SatoMakoto en-aut-sei=Sato en-aut-mei=Makoto kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=KimuraToshikiro en-aut-sei=Kimura en-aut-mei=Toshikiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil= kn-affil=Pharmaceutical Research Division, NIPRO Corporation affil-num=2 en-affil= kn-affil=Pharmaceutical Research Division, NIPRO Corporation affil-num=3 en-affil= kn-affil=Pharmaceutical Research Division, NIPRO Corporation affil-num=4 en-affil= kn-affil=Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University affil-num=5 en-affil= kn-affil=Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University affil-num=6 en-affil= kn-affil=bDepartment of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University affil-num=7 en-affil= kn-affil=Pharmaceutical Research Division, NIPRO Corporation affil-num=8 en-affil= kn-affil=Pharmaceutical Research Division, NIPRO Corporation affil-num=9 en-affil= kn-affil=Pharmaceutical Research Division, NIPRO Corporation affil-num=10 en-affil= kn-affil=Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Okayama University en-keyword=Recombinant human serum albumin (rHSA) kn-keyword=Recombinant human serum albumin (rHSA) en-keyword=PEG liposome kn-keyword=PEG liposome en-keyword=Doxorubicin kn-keyword=Doxorubicin en-keyword=Tumor-bearing rats kn-keyword=Tumor-bearing rats en-keyword=Passive targeting kn-keyword=Passive targeting END