ABSTRACT
Metal-organic complexes (MOCs) or metal-organic frameworks (MOFs) have attracted increasing interest for constructing nanoscale drug delivery systems for cancer therapy. However, conventional MOC/MOF materials usually contain toxic metals or low-biocompatible organic ligands. Also, current approaches for creating tumor-sensitive nanocarriers are always based on the instability of coordination bonds under acidic conditions, or through post-synthetic modification with sensitive molecules. As a matter of fact, it is more facile to fabricate tumor-sensitive MOCs/MOFs based on the stimuli-responsiveness of organic ligands. In this study, a novel tumor-sensitive biological MOC (bioMOC-Zn(Cys)) was created through the assembly of endogenous Zn2+ ions and the small biological molecule (l-cystine, Cys). The disulfide bond in l-cystine is cleavable by the overexpressed GSH in tumor cells, thus achieving rapid release of drugs from nanocarriers. By encapsulating doxorubicin (DOX) in bioMOC-Zn(Cys), DOX@bioMOC-Zn(Cys) displayed higher cellular uptake and cytotoxicity in cancer cells than free DOX. In vivo investigations indicated that DOX@bioMOC-Zn(Cys) largely inhibited tumor growth and reduced side effects. Remarkably, since both metal ions and organic ligands were obtained from biological sources, bioMOC-Zn(Cys) exhibited superior biocompatibility. This study presents a new method for fabricating MOC-based nanodrugs with high tumor-sensitivity and low toxicity.
Subject(s)
Antineoplastic Agents/chemistry , Biocompatible Materials/chemistry , Coordination Complexes/chemistry , Metal-Organic Frameworks/chemistry , Nanocapsules/chemistry , A549 Cells , Animals , Antineoplastic Agents/pharmacology , Cystine/chemistry , Cystine/metabolism , Disulfides/chemistry , Doxorubicin/chemistry , Doxorubicin/pharmacology , Drug Liberation , Female , Glutathione/chemistry , Glutathione/metabolism , Humans , Iron/chemistry , Iron/metabolism , Ligands , Mice, Inbred BALB C , Mice, Nude , Zinc/chemistry , Zinc/metabolism , Zirconium/chemistry , Zirconium/metabolismABSTRACT
The effective uptake and release of hydrophobic antitumor drugs in cancer cells is a practical challenge for tumor chemotherapy. Many methods were developed to conquer it through modifying drug molecules with hydrophilic groups, or fabricating nanodrugs based on hydrophilic materials. In recent years, peptides have attracted significant interest as part of a promising platform for fabricating nanodrugs due to their low cytotoxicity, favorable variability and self-assembly property. In this study, a cystine bridged peptide (CBP) was designed to co-assemble with a hydrophobic antitumor drug curcumin (CCM), to form a tumor-responsive nanodrug. The hydrophilicity of the peptide promotes the water-dispersity of nanodrugs, and the disulfide bond in cystine, which is cleavable by glutathione (GSH), was involved considering the overexpressed GSH in tumor microenvironments. In vitro and in vivo tests on cervical cancer cells revealed that the obtained nanodrug can rapidly dissociate at tumor sites and inhibit the tumor growth with limited side effects on healthy tissues.
Subject(s)
Antineoplastic Agents/pharmacology , Curcumin/pharmacology , Cystine/pharmacology , Peptides/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Cell Survival/drug effects , Curcumin/chemistry , Cystine/chemistry , Drug Liberation , Drug Screening Assays, Antitumor , Female , HeLa Cells , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Micelles , Nanoparticles/chemistry , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Peptides/chemical synthesis , Peptides/chemistryABSTRACT
Metal-organic frameworks (MOFs), which are a unique class of hybrid porous materials built from metal ions and organic ligands, have attracted significant interest in recent years as a promising platform for controlled drug delivery. Current approaches for creating MOFs-based responsive drug carriers involve encapsulation of stimuli-responsive compositions into MOFs or postsynthetic surface modification with sensitive molecules. In this study, we developed a novel intrinsic redox-responsive MOFs carrier, MOF-M(DTBA) (M = Fe, Al or Zr) by using iron, aluminum, or zirconium as metal nodes and 4,4'-dithiobisbenzoic acid (4,4'-DTBA) as the organic ligand. The disulfide bond in 4,4'-DTBA is cleavable by glutathione (GSH), which is often overexpressed in tumor cells. It was found that MOF-Zr(DTBA) synthesized at 40 °C displayed the appropriate size and properties as a drug carrier. By incorporating curcumin (CCM) into MOF-Zr(DTBA), CCM@MOF-Zr(DTBA) nanoparticles were obtained that displayed a faster releasing behavior in vitro and enhanced the cell death compared with free CCM. The in vivo anticancer experiments indicate that CCM@ MOF-Zr(DTBA) exhibits much higher antitumor efficacy than free CCM. This strategy for constructing responsive MOFs-based nanocarriers might open new possibilities for the application of MOFs in drug delivery, molecular imaging, or theranostics.
