RESUMO
The condensed version: Thiolated glycol chitosan can form stable nanoparticles with polymerized siRNAs through charge-charge interactions and self-cross-linking (see scheme). This poly-siRNA/glycol chitosan nanoparticles (psi-TGC) provided sufficient inâ vivo stability for systemic delivery of siRNAs. Knockdown of tumor proteins by psi-TGC resulted in a reduction in tumor size and vascularization.
Assuntos
Quitosana/química , Nanopartículas/química , Neoplasias/terapia , Interferência de RNA , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/uso terapêutico , Animais , Linhagem Celular Tumoral , Terapia Genética , Humanos , Camundongos , Neoplasias/genética , Neoplasias/patologia , RNA Interferente Pequeno/genética , Compostos de Sulfidrila/química , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
The safe and effective systemic delivery of siRNA is a prerequisite for the successful development of siRNA-based cancer therapeutics. For the enhanced delivery of siRNA, cationic lipids and polymers have been widely used as siRNA carriers to form electrolyte complexes with anionic siRNA. However, the considerable toxicity of strong cationic-charged molecules hampers their clinical use. In this study, we utilized human serum albumin (HSA), which is the most abundant of the plasma proteins, as a siRNA carrier for systemic tumor-targeted siRNA delivery. Both HSA and siRNA molecules were thiol-introduced to improve the binding affinity for each other. The resulting thiolated HSA (tHSA) and polymerized siRNA (psi) formed stable nanosized complexes (psi-tHSAs) by chemical crosslinking and self-crosslinking. After internalization, the psi-tHSAs showed target gene silencing activity in vitro comparable to conventional Lipofectamine™-siRNA complexes, without remarkable cytotoxicity. After intravenous injection in tumor-bearing mice, psi-tHSAs accumulated specifically at the tumor sites, leading to efficient gene silencing in the tumors in a sequential manner. The therapeutic VEGF siRNA was loaded into psi-tHSAs, which significantly inhibited tumor-related angiogenesis in PC-3 tumor xenografts and resulted in retarding the growth of PC-3 tumors. The results showed that self-crosslinked psi-tHSA nanocarriers might provide a promising approach for the systemic siRNA therapy of various human cancers.
Assuntos
Portadores de Fármacos/química , Neoplasias/terapia , Interferência de RNA , RNA Interferente Pequeno/administração & dosagem , Albumina Sérica/química , Animais , Linhagem Celular Tumoral , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Moleculares , Neoplasias/irrigação sanguínea , Neoplasias/genética , Neovascularização Patológica/genética , Neovascularização Patológica/terapia , Polimerização , RNA Interferente Pequeno/química , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/uso terapêutico , Compostos de Sulfidrila/química , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
Herein, we developed the photosensitizer, protoporphyrin IX (PpIX), conjugated glycol chitosan (GC) nanoparticles (PpIX-GC-NPs) as tumor-homing drug carriers with cellular on/off system for photodynamic imaging and therapy, simultaneously. In order to prepare PpIX-GC-NPs, hydrophobic PpIXs were chemically conjugated to GC polymer and the amphiphilic PpIX-GC conjugates formed a stable nanoparticle structure in aqueous condition, wherein conjugated PpIX molecules formed hydrophobic inner-cores and they were covered by the hydrophilic GC polymer shell. Based on the nanoparticle structure, PpIX-GC-NPs showed the self-quenching effect that is 'off' state with no fluorescence signal and phototoxicity with light exposure. It is due to the compact crystallized PpIX molecules in the nanoparticles as confirmed by dynamic light scattering and X-ray diffraction methods. However, after cellular uptake, compact nanoparticle structure gradually decreased to generate strong fluorescence signal and singlet oxygen generation when irradiated. Importantly, PpIX-GC-NPs-treated mice presented prolonged blood circulation, enhanced tumor targeting ability, and improved in vivo therapeutic efficiency in tumor-bearing mice, compared to that of free PpIX-treated mice. These results proved that this tumor-homing cellular 'on/off' nanoparticle system of PpIX-GC-NPs has a great potential for synchronous photodynamic imaging and therapy in cancer treatment.