ABSTRACT
Nanomedicines (NMs) offer new solutions for cancer diagnosis and therapy. However, extension of progression-free interval and overall survival time achieved by Food and Drug Administration-approved NMs remain modest. To develop next generation NMs to achieve superior anticancer activities, it is crucial to investigate and understand the correlation between the physicochemical properties of NMs (particle size in particular) and their interactions with biological systems to establish criteria for NM optimization. Here, we systematically evaluated the size-dependent biological profiles of three monodisperse drug-silica nanoconjugates (NCs; 20, 50, and 200 nm) through both experiments and mathematical modeling and aimed to identify the optimal size for the most effective anticancer drug delivery. Among the three NCs investigated, the 50-nm NC shows the highest tumor tissue retention integrated over time, which is the collective outcome of deep tumor tissue penetration and efficient cancer cell internalization as well as slow tumor clearance, and thus, the highest efficacy against both primary and metastatic tumors in vivo.
Subject(s)
Antineoplastic Agents/chemistry , Nanomedicine , Particle Size , Animals , Antineoplastic Agents/therapeutic use , Humans , MCF-7 Cells , Mice, Nude , Nanoconjugates , Neoplasm Metastasis , Neoplasms/drug therapy , Silicon Dioxide/chemistry , Tissue Distribution , Xenograft Model Antitumor AssaysSubject(s)
Drug Delivery Systems , Inflammation/drug therapy , Nanoparticles/administration & dosage , RNA, Small Interfering/administration & dosage , Tumor Necrosis Factor-alpha/administration & dosage , Administration, Oral , Animals , Base Sequence , Cell Line , Humans , Microscopy, Electron, Scanning , Molecular Sequence Data , Particle SizeSubject(s)
Aptamers, Nucleotide/chemistry , Lymph Nodes/diagnostic imaging , Nanoconjugates/chemistry , Silicon Dioxide/chemistry , Animals , Breast Neoplasms/diagnostic imaging , Breast Neoplasms/pathology , Cell Line, Tumor , Female , Humans , Lymphatic Metastasis , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Multimodal Imaging , Nanoconjugates/ultrastructure , Positron-Emission Tomography , Rhodamines/chemistry , Spectroscopy, Near-Infrared , Tomography, X-Ray Computed , Transplantation, HeterologousABSTRACT
Diblock copolymers consisting of poly(ethylene glycol)-block-poly(γ-4-(((2-(piperidin-1-yl)ethyl)amino)methyl)benzyl-L-glutamate) (PEG-b-PVBLG-8) were synthesized and evaluated for their ability to mediate gene delivery in hard-to-transfect cells like IMR-90 human fetal lung fibroblasts and human embryonic stem cells (hESCs). The PEG-b-PVBLG-8 contained a membrane-disruptive, cationic, helical polypeptide block (PVBLG-8) for complexing with DNA and a hydrophilic PEG block to improve the biocompatibility of the gene delivery vehicle. The incorporation of PEG effectively reduced the toxicity of the helical PVBLG-8 block without dramatically compromising the polymer's ability to destabilize membranes or form complexes with DNA. PEG-b-PVBLG-8 copolymers with low (n = 76) and high (n = 287) degrees of polymerization (n) of the PVBLG-8 block were synthesized and evaluated for gene delivery. PEG-b-PVBLG-8 diblock polymers with a high degree of polymerization have a greater transfection efficiency and lower toxicity in IMR-90 cells than the commercial reagent Lipofectamine 2000. The usefulness of PEG-b-PVBLG-8 was further demonstrated via the successful transfection of hESCs without a measured loss in cell pluripotency markers.