Targeted intracellular codelivery of chemotherapeutics and nucleic acid with a well-defined dendrimer-based nanoglobular carrier.

Codelivery of different therapeutics has a potential to efficaciously treat human diseases via their synergetic effects. We have recently developed a new class dendrimers, poly(l-lysine) dendrimers with a silsesquioxane cubic core (nanoglobules). These dendrimers have compact globular and well-defined structures and highly functionalized surfaces, and can be used as versatile carriers for biomedical applications. In this study, a generation-3 (G3) nanoglobular dendrimer was used to conjugate a peptide c(RGDfK) with a PEG spacer for codelivery of doxorubicin (DOX) and siRNA. Doxorubicin (DOX) was coupled to the RGD targeted nanoglobule via a degradable disulfide spacer to give G3-[PEG-RGD]-[DOX]. G3-[PEG-RGD]-[DOX] showed higher cytotoxicity than free DOX at high doses in glioblastoma U87 cells. G3-[PEG-RGD]-[DOX] was further complexed with siRNA and such complexes were readily internalized by U87 cells as shown by confocal microscopy. The siRNA complexes of the targeted conjugate resulted in significantly higher gene silencing efficiency in U87-Luc cells than those of control conjugates G3-[PEG-RGD] and G3-[DOX]. The nanoglobules are promising carriers for the codelivery of nucleic acids and chemotherapeutic agents.

[1]  Y. Bae,et al.  Self-assembled polyethylenimine-graft-poly(epsilon-caprolactone) micelles as potential dual carriers of genes and anticancer drugs. , 2007, Biomaterials.

[2]  D. Gewirtz,et al.  A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. , 1999, Biochemical pharmacology.

[3]  D. Parker,et al.  Synthesis and evaluation of globular Gd-DOTA-monoamide conjugates with precisely controlled nanosizes for magnetic resonance angiography. , 2008, Biomacromolecules.

[4]  K. Harada,et al.  Repetitive doxorubicin treatment of glioblastoma enhances the PGP expression--a special role for endothelial cells. , 2003, Experimental and toxicologic pathology : official journal of the Gesellschaft fur Toxikologische Pathologie.

[5]  Zheng-Rong Lu,et al.  Targeted systemic delivery of a therapeutic siRNA with a multifunctional carrier controls tumor proliferation in mice. , 2009, Molecular pharmaceutics.

[6]  A. Seifalian,et al.  Polyhedral Oligomeric Silsesquioxane Nanocomposites: The Next Generation Material for Biomedical Applications , 2006 .

[7]  Arwin J. Brouwer,et al.  Synthesis of DOTA-conjugated multivalent cyclic-RGD peptide dendrimers via 1,3-dipolar cycloaddition and their biological evaluation: implications for tumor targeting and tumor imaging purposes. , 2007, Organic and biomolecular chemistry.

[8]  Xu-li Wang,et al.  Synthesis, characterization, and gene delivery of poly-L-lysine octa(3-aminopropyl)silsesquioxane dendrimers: nanoglobular drug carriers with precisely defined molecular architectures. , 2007, Molecular pharmaceutics.

[9]  V. Torchilin,et al.  Tumor-specific anti-nucleosome antibody improves therapeutic efficacy of doxorubicin-loaded long-circulating liposomes against primary and metastatic tumor in mice. , 2009, Molecular pharmaceutics.

[10]  D. Wirtz,et al.  Efficient active transport of gene nanocarriers to the cell nucleus , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[11]  X. Wu,et al.  Development of solid lipid nanoparticles containing ionically complexed chemotherapeutic drugs and chemosensitizers. , 2004, Journal of pharmaceutical sciences.

[12]  Young Joo Kim,et al.  Preparation of a Promising Angiogenesis PET Imaging Agent: 68Ga-Labeled c(RGDyK)–Isothiocyanatobenzyl-1,4,7-Triazacyclononane-1,4,7-Triacetic Acid and Feasibility Studies in Mice , 2008, Journal of Nuclear Medicine.

[13]  Chenjie Xu,et al.  PET/MRI Dual-Modality Tumor Imaging Using Arginine-Glycine-Aspartic (RGD)–Conjugated Radiolabeled Iron Oxide Nanoparticles , 2008, Journal of Nuclear Medicine.

[14]  B. Szende,et al.  Induction of apoptosis in MDR1 expressing cells by daunorubicin with combinations of suboptimal concentrations of P-glycoprotein modulators. , 2001, Cancer letters.

[15]  G. Prestwich,et al.  Targeted Delivery of Doxorubicin by HPMA Copolymer-Hyaluronan Bioconjugates , 2002, Pharmaceutical Research.

[16]  Mark E. Davis,et al.  Quantitating intracellular transport of polyplexes by spatio-temporal image correlation spectroscopy. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Ho Sup Yoon,et al.  Co-delivery of drugs and DNA from cationic core–shell nanoparticles self-assembled from a biodegradable copolymer , 2006, Nature materials.

[18]  R. Marchant,et al.  Platelet and endothelial adhesion on fluorosurfactant polymers designed for vascular graft modification. , 2009, Journal of biomedical materials research. Part A.

[19]  R. Bendayan,et al.  In vitro investigation of ionic polysaccharide microspheres for simultaneous delivery of chemosensitizer and antineoplastic agent to multidrug-resistant cells. , 1999, Journal of pharmaceutical sciences.

[20]  M. Roberts,et al.  PDGF-regulated rab4-dependent recycling of alphavbeta3 integrin from early endosomes is necessary for cell adhesion and spreading. , 2001, Current biology : CB.

[21]  J. Kopeček,et al.  Comparison of the Anticancer Effect of Free and HPMA Copolymer-Bound Adriamycin in Human Ovarian Carcinoma Cells , 1999, Pharmaceutical Research.

[22]  D. Brooks,et al.  Conjugation to hyperbranched polyglycerols improves RGD-mediated inhibition of platelet function in vitro. , 2008, Bioconjugate chemistry.

[23]  J. Kopeček,et al.  Liberation of doxorubicin from HPMA copolymer conjugate is essential for the induction of cell cycle arrest and nuclear fragmentation in ovarian carcinoma cells. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[24]  Y. Bae,et al.  Self-assembled polyethylenimine-graft-poly(ε-caprolactone) micelles as potential dual carriers of genes and anticancer drugs , 2007 .

[25]  E. Jeong,et al.  Contrast-Enhanced MRI-Guided Photodynamic Cancer Therapy with a Pegylated Bifunctional Polymer Conjugate , 2008, Pharmaceutical Research.

[26]  Zheng-Rong Lu,et al.  A novel environment-sensitive biodegradable polydisulfide with protonatable pendants for nucleic acid delivery. , 2007, Journal of controlled release : official journal of the Controlled Release Society.

[27]  Steven Edward Kern,et al.  Combination of local, nonviral IL12 gene therapy and systemic paclitaxel treatment in a metastatic breast cancer model. , 2004, Molecular therapy : the journal of the American Society of Gene Therapy.

[28]  H. Yamagishi,et al.  Electrochemo-gene therapy of cancer: intratumoral delivery of interleukin-12 gene and bleomycin synergistically induced therapeutic immunity and suppressed subcutaneous and metastatic melanomas in mice. , 2003, Molecular therapy : the journal of the American Society of Gene Therapy.

[29]  Sanjiv S. Gambhir,et al.  Dual-Function Probe for PET and Near-Infrared Fluorescence Imaging of Tumor Vasculature , 2007, Journal of Nuclear Medicine.

[30]  F. Feher.  Controlled cleavage of R8Si8O12 frameworks: a revolutionary new method for manufacturing precursors to hybrid inorganic–organic materials , 1998 .

[31]  P. Choyke,et al.  Synthesis, characterization, and biological evaluation of integrin alphavbeta3-targeted PAMAM dendrimers. , 2008, Molecular pharmaceutics.