PURPOSES: To develop multifunctional RGD-decorated poly(ethylene oxide)-b-poly(ester) based micelles and assess their pH-triggered core degradation and targeted drug release in tumor cells that overexpress RGD receptors. METHODS: Novel poly(ethylene oxide)-b-poly(epsilon-caprolactone) (PEO-b-PCL) based copolymers modified with RGD ligands on PEO and pendent functional groups on PCL, i.e., GRGDS-PEO-b-poly(alpha-benzylcarboxylate-epsilon-caprolactone) (GRGDS-PEO-b-PBCL) and GRGDS-PEO-b-poly(alpha-carboxyl-epsilon-caprolactone) (GRGDS-PEO-b-PCCL), were synthesized. Chemical conjugation of doxorubicin (DOX) to PCCL core produced GRGDS-PEO-b-P(CL-DOX) micellar conjugates, while GRGDS-PEO-b-PBCL were used to physically encapsulate DOX. For both systems, micellar core degradation, drug release, intracellular drug uptake/disposition, and cytotoxicity against B16F10 metastatic cells were investigated. RESULTS: The PBCL and P(CL-DOX) cores were found resistant to degradation in pH 7.2, but showed 10% and 40% loss in core molecular weight in pH 5.0 within 144 h, respectively. Preferential release of DOX and DOX derivatives from PBCL and P(CL-DOX) cores was noted in pH 5.0, respectively. The GRGDS-modified micelles showed enhanced cellular internalization through endocytosis, increased intracellular DOX release, nuclear localization, and improved cytotoxicity against metastatic B16F10 cells compared to their unmodified counterparts. CONCLUSIONS: The results clearly suggest a promise for the development of multifunctional polymeric micelles with RGD ligand decorated shell and endosomal pH-triggered degradable core for selective DOX delivery to metastatic cancer cells.
PURPOSES: To develop multifunctional RGD-decorated poly(ethylene oxide)-b-poly(ester) based micelles and assess their pH-triggered core degradation and targeted drug release in tumor cells that overexpress RGD receptors. METHODS: Novel poly(ethylene oxide)-b-poly(epsilon-caprolactone) (PEO-b-PCL) based copolymers modified with RGD ligands on PEO and pendent functional groups on PCL, i.e., GRGDS-PEO-b-poly(alpha-benzylcarboxylate-epsilon-caprolactone) (GRGDS-PEO-b-PBCL) and GRGDS-PEO-b-poly(alpha-carboxyl-epsilon-caprolactone) (GRGDS-PEO-b-PCCL), were synthesized. Chemical conjugation of doxorubicin (DOX) to PCCL core produced GRGDS-PEO-b-P(CL-DOX) micellar conjugates, while GRGDS-PEO-b-PBCL were used to physically encapsulate DOX. For both systems, micellar core degradation, drug release, intracellular drug uptake/disposition, and cytotoxicity against B16F10 metastatic cells were investigated. RESULTS: The PBCL and P(CL-DOX) cores were found resistant to degradation in pH 7.2, but showed 10% and 40% loss in core molecular weight in pH 5.0 within 144 h, respectively. Preferential release of DOX and DOX derivatives from PBCL and P(CL-DOX) cores was noted in pH 5.0, respectively. The GRGDS-modified micelles showed enhanced cellular internalization through endocytosis, increased intracellular DOX release, nuclear localization, and improved cytotoxicity against metastatic B16F10 cells compared to their unmodified counterparts. CONCLUSIONS: The results clearly suggest a promise for the development of multifunctional polymeric micelles with RGD ligand decorated shell and endosomal pH-triggered degradable core for selective DOX delivery to metastatic cancer cells.
Authors: Praful R Nair; S A Karthick; Kyle R Spinler; Mohammad R Vakili; Afsaneh Lavasanifar; Dennis E Discher Journal: Nanomedicine (Lond) Date: 2016-05-13 Impact factor: 5.307
Authors: Amir H Soleimani; Shyam M Garg; Igor M Paiva; Mohammad R Vakili; Abdulraheem Alshareef; Yung-Hsing Huang; Ommoleila Molavi; Raymond Lai; Afsaneh Lavasanifar Journal: Drug Deliv Transl Res Date: 2017-08 Impact factor: 4.617
Authors: Muhammad Wahab Amjad; Mohd Cairul Iqbal Mohd Amin; Haliza Katas; Adeel Masood Butt Journal: Nanoscale Res Lett Date: 2012-12-28 Impact factor: 4.703