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Exosomes (Exo) hold great promise as endogenous nanocarriers that can deliver biological information between cells. However, Exo are limited in terms of their abilities to target specific recipient cell types. We developed a strategy to isolate Exo exhibiting increased binding to integrin αvβ3. Binding occurred through a modified version of a disintegrin and metalloproteinase 15 (A15) expressed on exosomal membranes (A15-Exo), which facilitated co-delivery of therapeutic quantities of doxorubicin (Dox) and cholesterol-modified miRNA 159 (Cho-miR159) to triple-negative breast cancer (TNBC) cells, both in vitro and in vivo. The targeted A15-Exo were derived from continuous protein kinase C activation in monocyte-derived macrophages. These cell-derived Exo displayed targeting properties and had a 2.97-fold higher production yield. In vitro, A15-Exo co-loaded with Dox and Cho-miR159 induced synergistic therapeutic effects in MDA-MB-231 cells. In vivo, miR159 and Dox delivery in a vesicular system effectively silenced the TCF-7 gene and exhibited improved anticancer effects, without adverse effects. Therefore, our data demonstrate the synergistic efficacy of co-delivering miR159 and Dox by targeted Exo for TNBC therapy. [ABSTRACT FROM AUTHOR]

Background: Macrophages with tumor-tropic migratory properties can serve as a cellular carrier to enhance the efficacy of anti neoplastic agents. However, limited drug loading (DL) and insufficient drug release at the tumor site remain the main obstacles in developing macrophage-based delivery systems. In this study, we constructed a biomimetic delivery system (BDS) by loading doxorubicin (DOX)-loaded reduced graphene oxide (rGO) into a mouse macrophage-like cell line (RAW264.7), hoping that the newly constructed BDS could perfectly combine the tumor-tropic ability of macrophages and the photothermal property of rGO. Results: At the same DOX concentration, the macrophages could absorb more DOX/PEG-BPEI-rGO than free DOX. The tumor-tropic capacity of RAW264.7 cells towards RM-1 mouse prostate cancer cells did not undergo significant change after drug loading in vitro and in vivo. PEG-BPEI-rGO encapsulated in the macrophages could effectively convert the absorbed near-infrared light into heat energy, causing rapid release of DOX. The BDS showed excellent anti-tumor efficacy in vivo. Conclusions: The BDS that we developed in this study had the following characteristic features: active targeting of tumor cells, stimuli-release triggered by near-infrared laser (NIR), and effective combination of chemotherapy and photothermotherapy. Using the photothermal effect produced by PEG-BPEI-rGO and DOX released from the macrophages upon NIR irradiation, MAs-DOX/PEG-BPEI-rGO exhibited a significant inhibitory effect on tumor growth. [ABSTRACT FROM AUTHOR]

Agents that chemically modify DNA form a backbone ofmany cancer treatments. A key problem for DNA-modifying agents islack of specificity. To address this issue, we designed novel molecularscaffolds, termed An-Hq and An-Hq2, which are activatedby a hallmark of some cancers: elevated concentrations of reactiveoxygen species. Elevated reactive oxygen species are linked to oncogenesisand are found to increase in several aggressive cancers. The agentsare quinones that, upon oxidation, form highly electrophilic species.In vitro studies identified the mode of addition to DNA. The anilineportion of An-Hq serves to enhance nucleophilic addition to the ethylphenyl ether instead of forming common Michael additions. Structuralcharacterization showed that the agents add to 2′-deoxyguanosineat the N2,N3-positions. The product formed is a bulky hydroxy-N2,3-benzetheno-2′-deoxyguanosineadduct. In addition, the oxidatively activated agents added to 2′-deoxyadenosineand 2′-deoxycytidine but not thymidine or 2′-deoxyinosine.These findings are confirmed by primer extension analysis of a 392base pair DNA. The full-length primer extension product was reducedby 69.0 ± 0.6% upon oxidative activation of An-Hq2as compared to controls. Little sequence dependence was observedwith 76% of guanine, adenine, and cytosine residues showing an increasein extension stops between 2- and 4-fold above controls. Benzetheno-nucleobaseaddition to double-stranded DNA was confirmed by LC/MS of a self-complementaryoligonucletide. Experiments were carried out to confirm in vivo DNAdamage. Because of the lesion identified in vitro, we reasoned thatnucleotide excision repair should be involved in reversing the effectsof these oxidatively activated agents and enhance toxicity in Drosophila melanogaster. Using an RNAi-based approach, Ercc1was silenced, and survival was monitored after injectionof an agent. As expected, bulky cross-linking DNA-modifying agents,cisplatin and chlorambucil, showed statistically significant enhancedtoxicity in Drosophila with silenced Ercc1. In addition,5-fluorouracil, which does not produce bulky lesions, showed no selectivetoxicity. An-Hq and An-Hq2showed statistically significanttoxicity in Drosophila with silenced Ercc1. Examinationof cytotoxicity shows renal carcinoma cell lines as a target of theseagents with a median IC50of 1.8 μM. Taken together,these data show that the designed oxidatively activated agents formdistinct, bulky DNA modifications that prove difficult for cancercells possessing an elevated reactive oxygen species phenotype toovercome. The modification produced is relatively unique among anticanceragents. [ABSTRACT FROM AUTHOR]