RESUMO
Photoactive MOF-based delivery systems are highly attractive for photodynamic therapy (PDT), but the fundamental interplay among structural parameters and photoactivity and biological properties of these MOFs remains unclear. Herein, porphyrinic MOF isomers (TCPP-MOFs), constructing using the same building blocks into distinct topologies, have been selected as ideal models to understand this problem. Both the intramolecular distances and molecular polarization within TCPP-MOFs isomers collectively contribute to the photoactivity of generating reactive oxygen species. Remarkably, the morphology-determined endocytic pathways and cytotoxicity, as well as good biocompatibility have been confirmed for TCPP-MOF isomers without any chemical modification for the first time. Besides the topology-dependent photoactive regulation, this work also provides in-depth insights into the biological effect from the MOF nanoparticles with controllable structural factors, benefiting further in vivo applications and clinical transformation.
Assuntos
Luz , Estruturas Metalorgânicas/química , Nanoestruturas/química , Porfirinas/química , Zircônio/química , Animais , Materiais Biocompatíveis/química , Materiais Biocompatíveis/metabolismo , Materiais Biocompatíveis/farmacologia , Caveolinas/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Endocitose , Feminino , Células HeLa , Hemólise/efeitos dos fármacos , Humanos , Estruturas Metalorgânicas/metabolismo , Estruturas Metalorgânicas/farmacologia , Camundongos , Distribuição TecidualRESUMO
Responsive drug delivery systems possess great potential in disease diagnosis and treatment. Herein, we develop an activatable prodrug and fluorescence imaging material by engineering the endogenous NAD(P)H:quinone oxidoreductase-1 (NQO1) responsive linker. The as-prepared nanomaterials possess the NQO1-switched drug release and fluorescence enablement, which realizes the tumor-specific chemotherapy and imaging in living mice. The enzyme-sensitive prodrug nanoparticles exhibit selectively potent anticancer performance to NQO1-positive cancer and ignorable off-target toxicity. This work provides an alternative strategy for constructing smart prodrug nanoplatforms with precision, selectivity, and practicability for advanced cancer imaging and therapy.
Assuntos
Antineoplásicos/farmacologia , Materiais Biocompatíveis/farmacologia , NAD(P)H Desidrogenase (Quinona)/metabolismo , Nanopartículas/química , Neoplasias/tratamento farmacológico , Medicina de Precisão , Pró-Fármacos/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Teste de Materiais , Camundongos , Estrutura Molecular , Neoplasias/diagnóstico por imagem , Neoplasias/metabolismo , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Imagem Óptica , Tamanho da Partícula , Pró-Fármacos/síntese química , Pró-Fármacos/químicaRESUMO
Oligoarginine is a class of cell-penetrating peptides known for their ability to enhance cellular uptake of different cargoes. Here, we aim to understand how differences in oligoarginine modifications affect the cellular internalization and subcellular trafficking of polymeric nanoparticles. We found that the length of oligoarginine not only influenced the rate of cellular uptake, but also directed the mechanism of endocytosis, endosomal escape and subcellular destinations. Confocal microscopy and flow cytometry analysis were conducted using submicron particles of poly(ethylene glycol)-b-poly(ε-caprolactone) (PEG-b-PCL) with the surface modified by 1-, 4- and 8-residue-long oligoarginines, designated as R1PECL, R4PECL and R8PECL respectively. R8PECL and R4PECL effectively increased cellular uptake by 12-fold and 5-fold, respectively, while the effect of R1 modification on the cellular uptake rate was negligible. Nanoparticles without oligoarginine and R1PECL particles entered cells via clathrin-mediated endocytosis and were both trapped in lysosomes. R4PECL particles were internalized via lipid-raft dependent endocytosis, but failed to escape from endosomes. R8PECL particles were taken up by both lipid-raft dependent endocytosis and macropinocytosis, and successfully escaped from endosomes to enter cytosol, ER and mitochondria. On the other hand, decreasing the degree of modification on the particle surface while keeping the length of oligoarginine only lowered the amount of uptake and endosomal escape, but did not alter the endocytic pathways and intracellular trafficking. In short, this study illustrates the effect of different surface modifications on the subcellular fate of polymeric nanoparticles, providing useful insights into the design of nanocarriers for subcellular targeting.
Assuntos
Endocitose/efeitos dos fármacos , Lactonas/toxicidade , Nanopartículas/metabolismo , Nanopartículas/toxicidade , Polietilenoglicóis/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Células HeLa , HumanosRESUMO
In this study, we present the preparation, characterization and application of a novel bioactive copolymer poly(l-lysine)-graft-folic acid-coupled poly(2-methyl-2-oxazoline) (PLL-g-PMOXA-c-FA), which has a specific interaction with folate receptor (FR)-positive cancer cells. Glass surface immobilized with PLL-g-PMOXA-c-FA was demonstrated to be adhesive to FR-positive cancer cells (HeLa, JEG-3) while nonadhesive to FR-negative ones (MCF-7, HepG2) in 3 h. The specific interaction between conjugated FA on the substrate and FRs on the cells could hardly be inhibited unless a high concentration (5 mM) of free FA was used due to the multivalent nature of it. The FA functionality ratio of the copolymer on the substrate had a significant influence on the adhesion of HeLa cells, and our experiments revealed that the affinity of the substrate to the cells declined dramatically with the decrease of functionality ratio. This was believed to be caused by the polydispersity of PMOXA tethers, as supported by GPC and ToF-SIMS data. As a proof of concept in the application of our material, we demonstrated successful recovery of HeLa cells from mixture with MCF-7 (1:100) on the copolymer-coated glass, and our results showed that both high sensitivity (95.6 ± 13.3%) and specificity (24.3 ± 8.6%) were achieved.
Assuntos
Técnicas Biossensoriais/métodos , Receptor 1 de Folato/química , Ácido Fólico/química , Neoplasias/química , Poliaminas/química , Polilisina/química , Técnicas Biossensoriais/instrumentação , Linhagem Celular Tumoral , Receptor 1 de Folato/metabolismo , Humanos , Cinética , Neoplasias/metabolismo , Polímeros/síntese química , Polímeros/químicaRESUMO
We prepared highly emissive and biocompatible dopamine-derived oligomers, and demonstrated their applications as novel fluorescent probes for sensitive detection of Fe(3+) ions and targeted bioimaging in live cells.