Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Doxorrubicina/uso terapêutico , Sistemas de Liberação de Medicamentos , Nanopartículas de Magnetita/química , Neoplasias/tratamento farmacológico , Animais , Antibióticos Antineoplásicos/química , Doxorrubicina/química , Camundongos , Modelos Moleculares , Estrutura Molecular , Tamanho da Partícula , Propriedades de SuperfícieAssuntos
Nanofibras/química , Células Neoplásicas Circulantes/metabolismo , Polímeros/química , Linhagem Celular Tumoral , Separação Celular , Eritrócitos/citologia , Humanos , Ácido Láctico/química , Melanoma/diagnóstico , Melanoma/metabolismo , Técnicas Analíticas Microfluídicas , Mutação , Células Neoplásicas Circulantes/química , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Análise de Célula ÚnicaRESUMO
A pretargeted oncologic positron emission tomography (PET) imaging that leverages the power of supramolecular nanoparticles with in vivo bioorthogonal chemistry was demonstrated for the clinically relevant problem of tumor imaging. The advantages of this approach are that (i) the pharmacokinetics (PKs) of tumor-targeting and imaging agents can be independently altered via chemical alteration to achieve the desired in vivo performance and (ii) the interplay between the two PKs and other controllable variables confers a second layer of control toward improved PET imaging. In brief, we utilized supramolecular chemistry to synthesize tumor-targeting nanoparticles containing transcyclooctene (TCO, a bioorthogonal reactive motif), called TCOâSNPs. After the intravenous injection and subsequent concentration of the TCOâSNPs in the tumors of living mice, a small molecule containing both the complementary bioorthogonal motif (tetrazine, Tz) and a positron-emitting radioisotope ((64)Cu) was injected to react selectively and irreversibly to TCO. High-contrast PET imaging of the tumor mass was accomplished after the rapid clearance of the unreacted (64)Cu-Tz probe. Our nanoparticle approach encompasses a wider gamut of tumor types due to the use of EPR effects, which is a universal phenomenon for most solid tumors.
Assuntos
Ciclo-Octanos/química , Glioblastoma/diagnóstico por imagem , Glioblastoma/diagnóstico , Compostos Heterocíclicos com 1 Anel/química , Nanopartículas/química , Tomografia por Emissão de Pósitrons/métodos , Animais , Radioisótopos de Cobre/administração & dosagem , Radioisótopos de Cobre/química , Dendrímeros/química , Glioblastoma/patologia , Compostos Heterocíclicos com 1 Anel/administração & dosagem , Humanos , Injeções Subcutâneas , Camundongos , Camundongos Nus , Nanopartículas/ultraestrutura , Transplante de Neoplasias , Permeabilidade , Polietilenos/química , Transplante HeterólogoRESUMO
Substrate-mediated gene delivery is a promising method due to its unique ability to preconcentrate exogenous genes onto designated substrates. However, many challenges remain to enable continuous and multiround delivery of the gene using the same substrates without depositing payloads and immobilizing cells in each round of delivery. Herein we introduce a gene delivery system, nanosubstrate-mediated delivery (NSMD) platform, based on two functional components with nanoscale features, including (1) DNAâSNPs, supramolecular nanoparticle (SNP) vectors for gene encapsulation, and (2) Ad-SiNWS, adamantane (Ad)-grafted silicon nanowire substrates. The multivalent molecular recognition between the Ad motifs on Ad-SiNWS and the ß-cyclodextrin (CD) motifs on DNAâSNPs leads to dynamic assembly and local enrichment of DNAâSNPs from the surrounding medium onto Ad-SiNWS. Subsequently, once cells settled on the substrate, DNAâSNPs enriched on Ad-SiNWS were introduced through the cell membranes by intimate contact with individual nanowires on Ad-SiNWS, resulting in a highly efficient delivery of exogenous genes. Most importantly, sequential delivery of multiple batches of exogenous genes on the same batch cells settled on Ad-SiNWS was realized by sequential additions of the corresponding DNAâSNPs with equivalent efficiency. Moreover, using the NSMD platform in vivo, cells recruited on subcutaneously transplanted Ad-SiNWS were also efficiently transfected with exogenous genes loaded into SNPs, validating the in vivo feasibility of this system. We believe that this nanosubstrate-mediated delivery platform will provide a superior system for in vitro and in vivo gene delivery and can be further used for the encapsulation and delivery of other biomolecules.
Assuntos
Técnicas de Transferência de Genes , Nanopartículas/química , Nanotecnologia/métodos , Motivos de Aminoácidos , Animais , Feminino , Vetores Genéticos , Células HEK293 , Células HeLa , Humanos , Células Jurkat , Luz , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência , Células NIH 3T3 , Tamanho da Partícula , Espalhamento de Radiação , beta-Ciclodextrinas/químicaRESUMO
Nanomaterials have been increasingly employed as drug(s)-incorporated vectors for drug delivery due to their potential of maximizing therapeutic efficacy while minimizing systemic side effects. However, there have been two main challenges for these vectors: (i) the existing synthetic approaches are cumbersome and incapable of achieving precise control of their structural properties, which will affect their biodistribution and therapeutic efficacies, and (ii) lack of an early checkpoint to quickly predict which drug(s)-incorporated vectors exhibit optimal therapeutic outcomes. In this work, we utilized a new rational developmental approach to rapidly screen nanoparticle (NP)-based cancer therapeutic agents containing a built-in companion diagnostic utility for optimal therapeutic efficacy. The approach leverages the advantages of a self-assembly synthetic method for preparation of two different sizes of drug-incorporated supramolecular nanoparticles (SNPs), and a positron emission tomography (PET) imaging-based biodistribution study to quickly evaluate the accumulation of SNPs at a tumor site in vivo and select the favorable SNPs for in vivo therapeutic study. Finally, the enhanced in vivo anti-tumor efficacy of the selected SNPs was validated by tumor reduction/inhibition studies. We foresee our rational developmental approach providing a general strategy in the search of optimal therapeutic agents among the diversity of NP-based therapeutic agents.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacocinética , Camptotecina/administração & dosagem , Camptotecina/farmacocinética , Portadores de Fármacos/química , Nanopartículas/química , Animais , Antineoplásicos Fitogênicos/uso terapêutico , Camptotecina/uso terapêutico , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/ultraestrutura , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Tomografia por Emissão de Pósitrons , Distribuição TecidualRESUMO
Nanoparticles are regarded as promising transfection reagents for effective and safe delivery of nucleic acids into a specific type of cells or tissues providing an alternative manipulation/therapy strategy to viral gene delivery. However, the current process of searching novel delivery materials is limited due to conventional low-throughput and time-consuming multistep synthetic approaches. Additionally, conventional approaches are frequently accompanied with unpredictability and continual optimization refinements, impeding flexible generation of material diversity creating a major obstacle to achieving high transfection performance. Here we have demonstrated a rapid developmental pathway toward highly efficient gene delivery systems by leveraging the powers of a supramolecular synthetic approach and a custom-designed digital microreactor. Using the digital microreactor, broad structural/functional diversity can be programmed into a library of DNA-encapsulated supramolecular nanoparticles (DNAâSNPs) by systematically altering the mixing ratios of molecular building blocks and a DNA plasmid. In vitro transfection studies with DNAâSNPs library identified the DNAâSNPs with the highest gene transfection efficiency, which can be attributed to cooperative effects of structures and surface chemistry of DNAâSNPs. We envision such a rapid developmental pathway can be adopted for generating nanoparticle-based vectors for delivery of a variety of loads.