RESUMEN
Tumor-targeted delivery and controlled release of antitumor drugs are promising strategies for increasing chemotherapeutic efficacy and reducing adverse effects. Although mesoporous silica nanoparticles (MSNs) have been known as a potential delivery system for doxorubicin (DOX), they have restricted applications due to their uncontrolled leakage and burst release from their large open pores. Herein, we engineered a smart drug-delivery system (smart MSN-drug) based on MSN-drug loading, cell membrane mimetic coating, on-demand pore blocking/opening, and tumor cell targeting strategies. The pore size of DOX-loaded MSNs was narrowed by polydopamine coating, and the pores/channels were blocked with tumor-targeting ligands anchored by tumor environment-rupturable -SS- chains. Furthermore, a cell membrane mimetic surface was constructed to enhance biocompatibility of the smart MSN-drug. Confocal microscopy results demonstrate highly selective uptake (12-fold in comparison with L929 cell) of the smart MSN-drug by HeLa cells and delivery into the HeLa cellular nuclei. Further in vitro IC50 studies showed that the toxicity of the smart MSN-drug to HeLa cells was 4000-fold higher than to the normal fibroblast cells. These exciting results demonstrate the utility of the smart MSN-drug capable of selectively killing tumor cells and saving the normal cells.
Asunto(s)
Antineoplásicos/farmacología , Doxorrubicina/farmacología , Portadores de Fármacos/química , Nanopartículas/química , Animales , Antineoplásicos/química , Doxorrubicina/química , Portadores de Fármacos/toxicidad , Liberación de Fármacos , Células HeLa , Humanos , Indoles/química , Indoles/toxicidad , Ratones , Nanopartículas/toxicidad , Fosforilcolina/análogos & derivados , Fosforilcolina/toxicidad , Polímeros/química , Polímeros/toxicidad , Porosidad , Dióxido de Silicio/química , Dióxido de Silicio/toxicidad , Microambiente Tumoral/fisiologíaRESUMEN
A versatile fabrication and performance optimization strategy of PEG and zwitterionic polymer coatings is developed on the sensor chip of surface plasma resonance (SPR) instrument. A random copolymer bearing phosphorylcholine zwitterion and active ester side chains (PMEN) and carboxylic PEG coatings with comparable thicknesses were deposited on SPR sensor chips via amidation coupling on the precoated polydopamine (PDA) intermediate layer. The PMEN coating showed much stronger resistance to bovine serum albumin (BSA) adsorption than PEG coating at very thin thickness (â¼1nm). However, the BSA resistant efficacy of PEG coating could exceed that of PMEN due to stronger steric repelling effect when the thickness increased to 1.5â¼3.3nm. Interestingly, both the PEG and PMEN thick coatings (≈3.6nm) showed ultralow fouling by BSA and bovine plasma fibrinogen (Fg). Moreover, changes in the PEG end group from -OH to -COOH, protein adsorption amount could increase by 10-fold. Importantly, the optimized PMEN and PEG-OH coatings were easily duplicated on other substrates due to universal adhesion of the PDA layer, showed excellent resistance to platelet, bacteria and proteins, and no significant difference in the antifouling performances was observed. These detailed results can explain the reported discrepancy in performances between PEG and zwitterionic polymer coatings by thickness. This facile and substrate-independent coating strategy may benefit the design and manufacture of advanced antifouling biomedical devices and long circulating nanocarriers. STATEMENT OF SIGNIFICANCE: Prevention of biofouling is one of the biggest challenges for all biomedical applications. However, it is very difficult to fabricate a highly hydrophilic antifouling coating on inert materials or large devices. In this study, PEG and zwitterion polymers, the most widely investigated polymers with best antifouling performance, are conveniently immobilized on different kinds of substrates from their aqueous solutions by precoating a polydopamine intermediate layer as the universal adhesive and readily re-modifiable surface. Importantly, the coating fabrication and antifouling performance can be monitored and optimized quantitatively by a surface plasma resonance (SPR) system. More significantly, the SPR on-line optimized coatings were successfully duplicated off-line on other substrates, and supported by their excellent antifouling properties.
Asunto(s)
Bacterias/metabolismo , Adhesión Bacteriana , Plaquetas/metabolismo , Materiales Biocompatibles Revestidos , Adhesividad Plaquetaria , Polietilenglicoles , Animales , Plaquetas/citología , Bovinos , Materiales Biocompatibles Revestidos/química , Materiales Biocompatibles Revestidos/farmacología , Humanos , Polietilenglicoles/química , Polietilenglicoles/farmacología , Albúmina Sérica BovinaRESUMEN
Phagocytic clearance and inefficient targeting are two major concerns for nanomedicines in cancer therapy. In this study, cell membrane inspired multifunctional copolymers (PMNCFs) were synthesized by a combination of cell membrane stealthy hydrophilic phosphorylcholine (PC), hydrophobic cholesterol (Chol) and tumor targeting folic acid (FA) functionalities on the different side chain ends. PMNCF micelles were prepared in aqueous solution to form a cell membrane mimetic structure with linked folic acid ligands as the protruding antennae on the surface of the micelles. Coumarin-6 loaded PMNCF micelles indicated that the mouse peritoneal macrophage cell uptake efficiency was suppressed to 1/10 compared with that of PLA nanoparticles. Doxorubicin loaded micelle measurements demonstrated that up to 30% of the drug could be obtained forming a stable formulation under both storage and physiological conditions. Tumor cell uptake and toxicity studies revealed that FA-decorated PMNCF micelles could increase MADB-106 cell uptake by 4-fold, and DOX loaded PMNCF micelles could kill tumor cells more efficiently than the same amount of free DOX. These exciting results confirmed the great potential of the stable, stealthy and tumor cell targeting PMNCF micelles for developing advanced long circulation and target-selective drug delivery nanoparticles.