Self-assembled Pt(II) metallacycles enable precise cancer combination chemotherapy.

Combination chemotherapy, which involves the simultaneous use of multiple anticancer drugs in adequate combinations to disrupt multiple mechanisms associated with tumor growth, has shown advantages in enhanced therapeutic efficacy and lower systemic toxicity relative to monotherapy. Herein, we employed coordination-driven self-assembly to construct discrete Pt(II) metallacycles as monodisperse, modular platforms for combining camptothecin and combretastatin A4, two chemotherapy agents with a disparate mechanism of action, in precise arrangements for combination chemotherapy. Formulation of the drug-loaded metallacycles with folic acid­functionalized amphiphilic diblock copolymers furnished nanoparticles with good solubility and stability in physiological conditions. Folic acids on the surface of the nanoparticles promote their internalization into cancer cells. The intracellular reductive environment of cancer cells induces the release of the drug molecules at an exact 1:1 ratio, leading to a synergistic anticancer efficacy. In vivo studies on tumor-bearing mice demonstrated the favorable therapeutic outcome and minimal side effects of the combination chemotherapy approach based on a self-assembled metallacycle.

pH-Responsive DNA nanoassembly for detection and combined therapy of tumor.

We have developed a novel cancer theragnostic nanoassembly with high biocompatibility, stability and low toxicity which are activated rapidly by tumor microenvironment to realize selective fluorescence imaging, chemotherapy as well as chemoenzymatic therapy. The nanoprobes are synthesized by hybridization of fluorophore labeled hairpin DNAs containing a 5-aza-dC at hemimethylated CpG sites and pH-sensitive DNA sequence covalently conjugated with PEGylated GO. The aptamer, which is also covalently conjugated on PEGylated GO, enables to target the tumor site and the weak acid environment of tumor triggers the release of drug loaded by nanoprobes including functionalized DNA and DOXs, effectively activating fluorescence signals and selectively killing the tumor cells. The results revealed that the nanoprobe enables sensitive detection of pH changes within subcellular environment, selectively imaging and great synergy of multicombination therapeutic including chemotherapy and chemoenzymatic therapy, implying that developed pH activatable probe has considerable potential for diagnosis and efficient therapy of cancer.

DNA-supramolecule conjugates in theranostics.

The elegant properties of deoxyribonucleic acid (DNA), such as accurate recognition, programmability and addressability, make it a well-defined and promising material to develop various molecular probes, drug delivery carriers and theranostic systems for cancer diagnosis and therapy. In addition, supramolecular chemistry, also termed "chemistry beyond the molecule", is a promising research field that aims to develop functional chemical systems by bringing discrete molecular components together in a manner that invokes noncovalent intermolecular forces, such as hydrophobic interaction, hydrogen bonding, metal coordination, and shape or size matching. Thus, DNA-supramolecule conjugates (DSCs) combine accurate recognition, programmability and addressability of DNA with the greater toolbox of supramolecular chemistry. This review discusses the applications of DSCs in sensing, protein activity regulation, cell behavior manipulation, and biomedicine.

Molecular Engineering-Based Aptamer-Drug Conjugates with Accurate Tunability of Drug Ratios for Drug Combination Targeted Cancer Therapy.

Polytherapy (or drug combination cancer therapy (DCCT)), targeting multiple mechanisms associated with tumor proliferation, can efficiently maximize therapeutic efficacy, decrease drug dosage, and reduce drug resistance. However, most DCCT strategies cannot coordinate the specific delivery of a drug combination in an accurately tuned ratio into cancer cells. To address these limitations, the present work reports the engineering of circular bivalent aptamer-drug conjugates (cb-ApDCs). The cb-ApDCs exhibit high stability, specific recognition, excellent cellular uptake, and esterase-triggered release. Furthermore, the drug ratios in cb-ApDCs can be tuned for an enhanced synergistic effect without the need for complex chemistry. Therefore, cb-ApDCs provide a promising platform for the development of DCCT strategies for different drug combinations and ratios.

Interaction of Anthracycline 3'-azido-epirubicin with Calf Thymus DNA via Spectral and Molecular Modeling Techniques.

Anthracycline antibiotics are extensively applied to clinical antitumor therapy. The binding mode and mechanism of a new anthracycline 3'-azido-epirubicin (AEPI) with calf thymus deoxyribonucleic acid (ctDNA) were investigated employing multiple spectroscopy techniques in Tris-HCl buffer solution (pH 7.4). Effect of pH on the interaction was provided to determine the proper environment for whole research. Iodide quenching studies and fluorescence polarization measurement indicated that ctDNA quenched the fluorescence of AEPI significantly via intercalation binding mode. The binding constants and binding sites for the interaction were calculated. From binding constant dependence on the temperature, static quenching mechanism of AEPI by ctDNA was confirmed based on the Stern-Volmer equation. Additionally, the thermodynamic parameters for the reaction revealed that the van der Waals force and hydrogen bonding were the main acting forces in the binding process. Molecular modeling result indicated that the hydrogen bonding played a major role in the binding of AEPI to ctDNA.

Side population cells isolated from KATO III human gastric cancer cell line have cancer stem cell-like characteristics.

AIM: To investigate whether the side population (SP) cells possess cancer stem cell-like characteristics in vitro and the role of SP cells in tumorigenic process in gastric cancer. METHODS: We analyzed the presence of SP cells in different human gastric carcinoma cell lines, and then isolated and identified the SP cells from the KATO III human gastric cancer cell line by flow cytometry. The clonogenic ability and self-renewal were evaluated by clone and sphere formation assays. The related genes were determined by reverse transcription polymerase chain reaction. To compare tumorigenic ability, SP and non-side population (NSP) cells from the KATO III human gastric cancer cell line were subcutaneously injected into nude mice. RESULTS: SP cells from the total population accounted for 0.57% in KATO III, 1.04% in Hs-746T, and 0.02% in AGS (CRL-1739). SP cells could grow clonally and have self-renewal capability in conditioned media. The expression of ABCG2, MDRI, Bmi-1 and Oct-4 was different between SP and NSP cells. However, there was no apparent difference between SP and NSP cells when they were injected into nude mice. CONCLUSION: SP cells have some cancer stem cell-like characteristics in vitro and can be used for studying the tumorigenic process in gastric cancer.

Side population cells from HXO-Rb44 retinoblastoma cell line have cancer-initiating property.

AIM: To ascertain whether side population (SP) cells in HXO-Rb44 retinoblastoma cell line have cancer stem cell-like property in vitro and in vivo. METHODS: We analyzed and sorted SP from HXO-Rb44 retinoblastoma cell line by Hoechst 33342 staining on flow cytometry. SP and NSP cells were determined their ability of proliferation and self-renewal by SP reanalysis, soft agar assay and tumor sphere assay in vitro. Clone formation was detected by seeding HXO-Rb44 and HXO-Rb44 -RFP cells into soft agar. The expression of ABCG2, MDRI, Bmi-1 and Oct-4 was determined by RT-PCR between SP and non-SP (NSP) cells. Moreover, they were injected into nude mice to determine their tumorigency in vivo. RESULTS: SP from HXO-Rb44 retinoblastoma cell line could grow clonally in soft agar assays and form tumor spheres from single cells in conditioned media. The expressions of ABCG2, MDRI, Bmi-1 and Oct-4 were significantly higher in SP than NSP cells. As few as SP cells resulted in tumor formation in 6 of 12 injected sites, however, the injection of NSP cells failed to form new tumor. CONCLUSION: SP cells isolated by Hoechst 33342 from the HXO-Rb44 retinoblastoma cell line had property of high tumorigency in vivo and in vitro. Therefore, SP might be a target while developing retinoblastoma therapies.