ABSTRACT
Chemotherapy for non-small-cell lung cancer (NSCLC) treatment has been employed over the past 20 years. However, poor water-solubility, low bioavailability and less drug accumulation of chemotherapeutic drugs restrict its antitumor activities in clinic. DNA nanostructures are proposed as drug carriers due to their intrinsic biocompatibility and programmability. In this work, we demonstrate a novel DNA nanocarrier grafted with erlotinib as an effective drug delivery system (DDS) for anti-cancer treatment. Specifically, erlotinib (Er), a hydrophobic small molecule drug targeting the epidermal growth factor receptor (EGFR), is covalently conjugated with azide (N3) modified DNA strands and subsequently self-assembled on spatially programmable erlotinib-grafted 6 × 6 × 64 nt DNA nanostructures. Thus, Er was successfully grafted on DNA carriers and transformed into a hydrophilic formulation. The antitumor efficacy was evaluated both in vitro and in vivo, and enhanced cytotoxicity toward A549 cells and the marked inhibition of tumor growth for non-small-cell lung cancer (NSCLC) were observed.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Nanostructures , Carcinoma, Non-Small-Cell Lung/drug therapy , Cell Line, Tumor , DNA , Erlotinib Hydrochloride , Humans , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors , Xenograft Model Antitumor AssaysABSTRACT
Cisplatin is a first-line drug in clinical cancer treatment but its efficacy is often hindered by chemoresistance in cancer cells. Reduced intracellular drug accumulation is revealed to be a major mechanism of cisplatin resistance. Nanoscale drug delivery systems could help to overcome this problem because of their more active cellular uptake and more accurate tumor localization. DNA nanostructures have emerged as promising drug delivery systems because of their intrinsic biocompatibility and structural programmability. Herein, three diverse DNA nanostructures are constructed and their potential for cisplatin prodrug delivery is investigated. Results found that these DNA nanostructures could remarkably enhance the cellular internalization of platinum drugs and thus increase the anticancer activity, not only to regular lung cancer cells (A549), but more importantly to cisplatin-resistant cancer cells (A549cisR). Further, in vivo studies also demonstrate that cisplatin prodrug loaded DNA nanostructures could effectively suppress tumor growth in both regular and cisplatin-resistant tumor models. This study suggests that DNA nanostructures are effective carriers for platinum prodrug delivery to combat chemoresistance.
Subject(s)
Antineoplastic Agents , Nanostructures , Prodrugs , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cisplatin/pharmacology , DNA , Drug Resistance, Neoplasm , Prodrugs/pharmacologyABSTRACT
DNA G-quadruplexes are not only attractive drug targets for cancer therapeutics, but also have important applications in supramolecular assembly. Here, we report a platinum(II)-based tripod (Pt-tripod) specifically binds the biological relevant hybrid-1 human telomeric G-quadruplex (Tel26), and strongly inhibits telomerase activity. Further investigations illustrate Pt-tripod induces the formation of monomeric and multimeric Pt-tripodâTel26 complex structures in solution. We solve the 1:1 and the unique dimeric 4:2 Pt-tripod-Tel26 complex structures by NMR. The structures indicate preferential binding of Pt-tripod to the 5'-end of Tel26 at a low Pt-tripod/Tel26 ratio of 0-1.0. After adding more Pt-tripod, the Pt-tripod binds the 3'-end of Tel26, unexpectedly inducing a unique dimeric 4:2 structure interlocked by an A:A non-canonical pair at the 3'-end. Our structures provide a structural basis for understanding the dynamic binding of small molecules with G-quadruplex and DNA damage mechanisms, and insights into the recognition and assembly of higher-order G-quadruplexes.
Subject(s)
G-Quadruplexes , Organoplatinum Compounds/chemistry , Platinum/chemistry , Solutions/chemistry , DNA/chemistry , Humans , Telomerase , Telomere/chemistryABSTRACT
Herein, two photosensitive platinum(II)-based tripods were designed and synthesized. Notably, complexâ 1 ({[Pt(dien)]3 L}(NO3 )6 , L=tri(4-pyridylphenyl)amine and dien=diethylenetriamine), which mainly accumulated in the cell nucleus, exhibited very low cytotoxicity in the absence of light irradiation, but displayed a remarkable increase in cytotoxicity upon visible light irradiation. Mechanistic investigations revealed that the tripod interacted with DNA in the nucleus, induced ROS generation upon light irradiation, and consequently elicited rapid DNA damage response; thereby triggering cancer cell apoptosis.
Subject(s)
Antineoplastic Agents/toxicity , Coordination Complexes/chemistry , DNA Damage/drug effects , Platinum/chemistry , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Line, Tumor , Coordination Complexes/chemical synthesis , Coordination Complexes/toxicity , Electron Spin Resonance Spectroscopy , G-Quadruplexes/drug effects , HeLa Cells , Humans , Light , Microscopy, Fluorescence, Multiphoton , Photochemotherapy , Photosensitizing Agents/chemical synthesis , Photosensitizing Agents/chemistry , Photosensitizing Agents/toxicity , Reactive Oxygen Species/metabolismABSTRACT
Two trigeminal star-like platinum complexes were synthesized to induce the formation of human telomere G-quadruplex (hTel G4) with extremely high selectivity and affinity. The induced hTel G4 activates strong telomeric DNA damage response (TDDR), resulting in telomere dysfunction and cell senescence.
Subject(s)
Cellular Senescence/drug effects , G-Quadruplexes/drug effects , Organoplatinum Compounds/pharmacology , Telomere/drug effects , Cell Line, Tumor , Dose-Response Relationship, Drug , Fluorescence Resonance Energy Transfer , Humans , Molecular Structure , Organoplatinum Compounds/chemical synthesis , Organoplatinum Compounds/chemistry , Structure-Activity Relationship , Telomere/metabolismABSTRACT
Two porphyrin-bridged tetranuclear platinum(II) complexes are found to effectively stabilize various kinds of G-quadruplexes. Their clover-like shape endows them with the capability of targeting G-quadruplexes rather than the double-stranded structure. Their excellent anticancer activity is the result of a dual effect, inhibition of the telomerase activity and repression of oncogene expression.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , G-Quadruplexes/drug effects , Organoplatinum Compounds/chemistry , Organoplatinum Compounds/pharmacology , Cell Cycle/drug effects , HeLa Cells , Humans , Neoplasms/drug therapy , Porphyrins/chemistry , Porphyrins/pharmacology , Telomerase/antagonists & inhibitorsABSTRACT
<p><b>OBJECTIVES</b>Knee osteoarthritis (OA) is a major cause of pain and functional limitation. Short-term Baduanjin () exercise had been testified to be beneficial to the disease. This study conducted an initial assessment of the one-year Baduanjin exercise on knee OA.</p><p><b>METHODS</b>The recruited patients practiced Baduanjin at the community recreational center. Sessions were held for 30 min five times a week for one year. Knee pain, stiffness, physical disability, general health, knee extensors and flexors strength, and aerobic ability were measured using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the Medical Outcomes Study Short Form-36 (SF-36), the 6-Minute Walk Test (6-MWT), and the Isokinetic Strength of the Knee Extensors and Flexors (ISKEF). Body mass index (BMI) was also calculated before and after the study period for comparison.</p><p><b>RESULTS</b>Twenty-eight patients signed the informed consent. Six patients withdrew from the trial. Twenty-two patients (29 knees) completed the one-year study. After one-year Baduanjin exercise, WOMAC pain (132.0±69.6 vs. 56.2±67.6, P=0.000), stiffness (64.7±54.8 vs. 22.3±34.6, P=0.000), and physical function subscales (386.1±275.8 vs. 182.0±235.7, P=0.003); SF-36 body pain (45.7±20.0 vs. 57.4±17.9, P=0.005), general health (50.5±20.0 vs. 62.1±16.1, P=0.004), role emotional (64.4±26.1 vs. 73.5±21.3, P=0.047), and health transition (3.3±1.0 vs. 2.6±1.0, P=0.008); BMI (25.0±2.9 vs. 24.4±2.9, P=0.032); 6-MWT (565.7±94.6 vs. 610.5±66.7, P=0.036); and ISKEF Peak Torque (the Knee Extensors: 60.5±25.5 vs. 76.8±31, P=0.000; the Knee Flexors: 29.3±15.9 vs. 37.1±15.8, P=0.001) were significantly improved. No adverse effects resulted from the exercise.</p><p><b>CONCLUSIONS</b>It suggested that the long-term Baduanjin could be a feasible and safe exercise option for knee OA.</p>
Subject(s)
Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Exercise Therapy , Osteoarthritis, Knee , TherapeuticsABSTRACT
A series of four self-assembled Pt(II) molecular squares with 4,4'-dipyridyl or pyrazine bridges, including the previously reported Pt(II) squares [Pt(en)(4,4'-dipyridyl)](4)(NO(3))(8) (1), were investigated for their abilities to act as selective and effective human telomeric (htelo) G-quadruplex binders. FRET and SPR studies demonstrated that Pt(II) squares could discriminate against duplex DNA, and show promising selectivity between intramolecular G-quadruplexes. PCR-stop assays and CD studies showed that Pt(II) squares strongly induced the formation of parallel G-quadruplexes. ITC experiments indicated that Pt(II) squares could bind to the G-quadruplex with high binding constants (K(b) values ranging from 10(4)-10(8) M(-1)). All four Pt(II) squares were effective inhibitors of human telomerase, and showed anticancer efficacy. This was particularly the case for [Pt(NH(3))(2)(4,4'-dipyridyl)](4)(NO(3))(8) (2), which exhibited a 15-fold higher antiproliferative effect on A549/cisR cells than cisplatin.
