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Despite the development of treatment options in breast cancer, many patients die of recurrence and metastasis. Owing to enhanced permeability and retention in solid tumor tissue, nanoparticle (NP) delivery systems have been emerged as novel strategy in cancer chemotherapy. As extracellular matrix, glycosaminoglycan hyaluronan (HA) could bind its surface receptor adhesion molecule CD44 which is strongly expressed on breast cancer. We have previously reported a doxorubicin (DOX)-loaded HA-Lys-LA X-NPs (X-NP-DOX) NP delivery system for breast cancer treatment. In this study, we further investigated the antitumor effect of X-NP-DOX NP delivery system using low-dose DOX in both in vitro and in vivo systems. We demonstrated that low-dose X-NP-DOX possessed the ability for inhibiting MCF-7 breast cancer cell growth, invasion, and migration, and inducing apoptosis in vitro. In in vivo experiments, injection of low-dose X-NP-DOX into tumor-bearing mouse resulted in significant reduction of tumor size. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining further revealed that low-dose X-NP-DOX induced higher percentage of apoptotic cells compared with free DOX or saline. Furthermore, our study demonstrated that low-dose X-NP-DOX inhibited Notch1 and Ras/MAPK pathways, decreased cancer stem cell population, and reduced tumorigenesis compared to free DOX in both in vitro and in vivo settings. Owing to its enhanced efficacy and higher targetability compared to free DOX, low-dose DOX delivered by NP system may be a promising novel strategy for breast cancer treatment.

Near-infrared light is an attractive stimulus due to its noninvasive and deep tissue penetration. Particularly, NIR light is utilized for cancer thermotherapy and on-demand release of drugs by the disruption of the delivery carriers. Here we have prepared a novel NIR-responsive DNA-hybrid-gated nanocarrier based on mesoporous silica-coated Cu1.8S nanoparticles. Cu1.8S nanoparticles, possessing high photothermal conversion efficiency under a 980 nm laser, were chosen as photothermal agents. The mesoporous silica structure could be used for drug storage/delivery and modified with aptamer-modified GC-rich DNA-helix as gatekeepers, drug vectors, and targeting ligand. Simultaneously, the as-produced photothermal effect caused denaturation of DNA double strands, which triggered the drug release of the DNA-helix-loaded hydrophilic drug doxorubicin and mesopore-loaded hydrophobic drug curcumin, resulting in a synergistic therapeutic effect. The Cu1.8S@mSiO2 nanocomposites endocytosed by cancer cells through the aptamer-mediated mode are able to generate rational release of doxorubicin/curcumin under NIR irradiation, strongly enhancing the synergistic growth-inhibitory effect of curcumin against doxorubicin in MCF-7 cells, which is associated with a strong mitochondrial-mediated cell apoptosis progression. The underlying mechanism of apoptosis showed a strong synergistic inhibitory effect both on the expression of Bcl-2, Bcl-xL, Mcl-1, and upregulated caspase 3/9 activity and on the expression level of Bak and Bax. Therefore, Cu1.8S@mSiO2 with efficient synergistic therapeutic efficiency is a potential multifunctional cancer therapy nanoplatform.

Combining the multi-modal medical imaging with cancer therapy in one single system has attracted the great interests for theranostic purpose. In this paper, CaF2:Yb(3+)/Er(3+)/Mn(2+)-poly(2-Aminoethyl methacrylate) (UCHNs-PAMA) hybrid microspheres were successfully fabricated. The synthetic route to the nanocomposite based on a facile hydrothermal method for fabrication of hollow upconversion (UC) nanospheres at first and then post-filling the PAMA interiorly through photo-initiated polymerization. The UCHNs showed orange fluorescence under 980 nm near infrared (NIR) laser excitation, which provided the upconverting luminescence (UCL) imaging modality. Meanwhile, the presence of functional Mn(2+) and Yb(3+) offered the enhanced T1-weighted magnetic resonance (MR) and computed tomography (CT) imaging, respectively. Thanks to introducing amine groups-containing PAMA inside the hollow nanospheres, the Pt(IV) pro-drug, c,c,t-Pt(NH3)2Cl2(OOCCH2CH2COOH)2 (DSP), can be conveniently bonded on the polymer network to construct a nanoscale anti-cancer drug carrier. The UCHNs-PAMA-Pt(IV) nanocomposite shows effective inhibition for Hela cell line via MTT assay. In contrast, Pt(IV) pro-drug and UCHNs-PAMA microspheres behave little cytotoxicity to Hela cells. This should be attributed the fact that the anti-cancer ability can be recovered only when Pt(IV) pro-drug was reduced to Pt(II)-drug in cellular environment. Furthermore, the in vivo experiments on small mice also confirm that the hybrid microspheres have relatively low toxic side effects and high tumor inhibition rate. These findings show that the multifunctional hybrid microspheres have potential to be used as UCL/MR/CT tri-modal imaging contrast agent and anti-cancer drug carriers., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

To overcome the side effects of and resistance to cisplatin, a variety of Pt(IV) prodrugs were designed and synthesized via different modifications including combination with lipid chains to increase hydrophobicity, conjugation with short peptide chains or nanoparticles to improve drug delivery, or addition of bioactive ligands to the axial positions of Pt(IV) complexes to exert dual-function effects. This review summarizes the recent progress in the development of Pt(IV) prodrugs conjugated with bioactive-targeting ligands, including histone deacetylase inhibitors, p53 agonists, alkylating agents, and nonsteroidal anti-inflammatory agents. Although Pt(IV) complexes that conjugated with bioactive ligands show satisfactory anticancer effects, none has been approved for clinical use. Therefore, we hope that this review will contribute to further study and development of Pt(IV) complexes conjugated with bioactive and other ligands. [ABSTRACT FROM AUTHOR]

Multifunctional nanocarriers based on the up-conversion luminescent nanoparticles of NaYF4:Yb3+/Er3+ core (UCNPs) and thermo/pH-coupling sensitive polymer poly[( N-isopropylacrylamide)- co-(methacrylic acid)] (P(NIPAm- co-MAA)) gated mesoporous silica shell are reported for cancer theranostics, including fluorescence imaging, and for controlled drug release for therapy. The as-synthesized hybrid nanospheres UCNPs@mSiO2-P(NIPAm- co-MAA) show bright green up-conversion fluorescence under 980 nm laser excitation and the thermo/pH-sensitive polymer is active as a 'valve' to moderate the diffusion of the embedded drugs in-and-out of the pore channels of the silica container. The anticancer drug doxorubicin hydrochloride (DOX) can be absorbed into UCNPs@mSiO2-P(NIPAm- co-MAA) nanospheres and the composite drug delivery system (DDS) shows a low level of leakage at low temperature/high pH values but significantly enhanced release at higher temperature/lower pH values, exhibiting an apparent thermo/pH controlled 'on-off' drug release pattern. The as-prepared UCNPs@mSiO2-P(NIPAm- co-MAA) hybrid nanospheres can be used as bioimaging agents and biomonitors to track the extent of drug release. The reported multifunctional nanocarriers represent a novel and versatile class of platform for simultaneous imaging and stimuli-responsive controlled drug delivery. [ABSTRACT FROM AUTHOR]

Multifunctional nanocarriers for targeted bioimaging and drug delivery have attracted much attention in early diagnosis and therapy of cancer. In this work, we develop a novel aptamer-guided nanocarrier based on the mesoporous metal-organic framework (MOF) shell and up-conversion luminescent NaYF4:Yb3+/Er3+ nanoparticles (UCNPs) core for the first time to achieve these goals. These UCNPs, chosen as optical labels in biological assays and medical imaging, could emit strong green emission under 980 nm laser. The MOF structure based on iron (III) carboxylate materials [MIL-100 (Fe)] possesses high porosity and non-toxicity, which is of great value as nanocarriers for drug storage/delivery. As a unique nanoplatform, the hybrid inorganic-organic drug delivery vehicles show great promising for simultaneous targeted labeling and therapy of cancer cells. [ABSTRACT FROM AUTHOR]

Porous hydroxyapatite (HAp) compositefibers functionalized withup-conversion (UC) luminescent and magnetic Na(Y/Gd)F4:Yb3+,Er3+nanocrystals (NCs) have been fabricatedvia electrospinning. After transferring hydrophobic oleic acid-cappedNa(Y/Gd)F4:Yb3+,Er3+NCs into aqueoussolution, these water-dispersible NCs were dispersed into precursorelectrospun solution containing CTAB. Na(Y/Gd)F4:Yb3+,Er3+@HAp composite fibers were fabricated bythe high temperature treatment of the electrospun Na(Y/Gd)F4:Yb3+,Er3+NCs decorated precursor fibers.The biocompatibility test on MC 3T3-E1 cells using MTT assay showsthat the HAp composite fibers have negligible cytotoxity, which revealsthe HAp composite fibers could be a drug carrier for drug delivery.Because the contrast brightening is enhanced at increased concentrationsof Gd3+, the HAp composite fibers can serve as T1magnetic resonance imaging contrast agents. In addition, the compositesuptaken by MC 3T3-E1 cells present the UC luminescent emission ofEr3+under the excitation of a 980 nm near-infrared laser.The above findings reveal Na(Y/Gd)F4:Yb3+,Er3+@HAp composite fibers have potential applications in drugstorage/release and magnetic resonance/UC luminescence imaging. [ABSTRACT FROM AUTHOR]