Lanthanide-doped upconversion materials, capable of converting low-density (< 1000 W cm À2 ) near-infrared (NIR) excitation to ultraviolet (UV) and visible emissions, have generated a large amount of interests in the areas of information technology, biotechnology, energy, and photonics. [1] Significantly, recent developments in the synthetic and multicolor tuning methods have allowed easy access to upconversion nanoparticles with well-defined phase and size, core-shell structure, optical emission, and surface properties. [2][3][4][5] The technological advances provide promising applications in sensitive biodetection and advanced bioimaging without many of the constraints associated with conventional optical biolabels. [6] Despite the attractions, further progress in using upconversion processes has been largely hindered because upconversion nanoparticles are typically sensitized by Yb 3+ ions that only respond to narrowband NIR excitation centered at 980 nm. The absorption of 980 nm light by the water component in biological samples usually limits deep tissue imaging and induces potential thermal damages to cells and tissues. [7] Excitation of conventional upconversion nanoparticles at other wavelengths has been proposed to minimize the effect of water absorption. [8] But the use of this technique is limited mainly by the largely sacrificed excitation efficiency. Efforts have also been devoted to tuning the NIR response of photon upconversion through integration of various sensitizers such as metal ions (e.g.; Nd 3+ , V 3+ or Cr 5+ ) and organic dyes. [9] The progress has resulted in visible emission by NIR excitation in the 700-900 nm range where the transparency of biological samples is maximal. [9e-h] However, upconversion emission across a broad range of spectra in these systems have not been demonstrated largely owing to the uncontrollable nonradiative processes. Herein, we describe a novel design, based on nanostructural engineering to separate unwanted electronic transitions for constructing a new class of materials displaying tunable upconversion emissions spanning from UV to the visible spectral region by single wavelength excitation at 808 nm. We also show that these nanoparticles can surpass the constraints associated with conventional upconversion nanoparticles for biological studies.The nanostructure design for management of energy transitions is depicted in Figure 1. A core-shell-shell nanoparticle platform is used to host light-harvesting, upconverting, and optical tuning processes at separate layers through doping of appropriate lanthanide ions. Interlayer energy exchange interactions are mediated by arrays of lanthanide migrator ions that can bridge efficient energy transfer across the core-shell interface while filtering unwanted crossrelaxations. As a result, incompatible optical processes can be rationally combined to achieve flexible and efficient photon energy conversions.As a proof-of-concept experiment, we employed a NaYbF 4 @Na(Yb,Gd)F 4 @NaGdF 4 core-shell-shell nanoparticle host....
Techniques for introducing foreign molecules and materials into living cells are of great value in cell biology research. A major barrier for intracellular delivery is to cross the cell membrane. Here we demonstrate a novel platform utilizing diamond nanoneedle arrays to facilitate efficient vector-free cytosolic delivery. Using our technique, cellular membrane is deformed by an array of nanoneedles with a force on the order of a few nanonewtons. We show that this technique is applicable to deliver a broad range of molecules and materials into different types of cells, including primary neurons in adherent culture. Especially, for delivering plasmid DNAs into neurons, our technique produces at least eightfold improvement (B45% versus B1-5%) in transfection efficiency with a dramatically shorter experimental protocol, when compared with the commonly used lipofection approach. It is anticipated that our technique will greatly benefit basic research in cell biology and also a wide variety of clinical applications.
DNA is a major target of anticancer drugs. The resulting adducts interfere with key cellular processes, such as transcription, to trigger downstream events responsible for drug activity. cisDiammine(pyridine)chloroplatinum(II), cDPCP or pyriplatin, is a monofunctional platinum(II) analogue of the widely used anticancer drug cisplatin having significant anticancer properties with a different spectrum of activity. Its novel structure-activity properties hold promise for overcoming drug resistance and improving the spectrum of treatable cancers over those responsive to cisplatin. However, the detailed molecular mechanism by which cells process DNA modified by pyriplatin and related monofunctional complexes is not at all understood. Here we report the structure of a transcribing RNA polymerase II (pol II) complex stalled at a site-specific monofunctional pyriplatin-DNA adduct in the active site. The results reveal a molecular mechanism of pol II transcription inhibition and drug action that is dramatically different from transcription inhibition by cisplatin and UV-induced 1,2-intrastrand cross-links. Our findings provide insight into structure-activity relationships that may apply to the entire family of monofunctional DNA-damaging agents and pave the way for rational improvement of monofunctional platinum anticancer drugs.anticancer | chemotherapy | DNA damage | pyriplatin | transcription T he DNA template for transcription is not only the site of inborn errors of metabolism and of continuous attack by harmful environmental agents, but it also represents a major target for cancer therapy. Platinum-based anticancer drugs such as cisplatin, cis-diamminedichloroplatinum(II), are widely used and among the most effective antineoplastic treatments (1, 2). Platinum-based drugs typically form bifunctional intra-or interstrand DNA cross-links by covalent bonding to the N 7 positions of two guanosine residues, triggering a variety of cellular processes, including transcription inhibition with attendant apoptosis (1, 2). However, resistance and side effects can require withdrawal of these drugs before they can effect a cure in certain types of cancer (3).In the effort to find new compounds that circumvent resistance to conventional bifunctional platinum-based drugs, a class of monofunctional platinum compounds were synthesized and screened for anticancer activity (4-6). In contrast to other inactive monofunctional platinum(II) compounds such as ½PtðdienÞCl þ and ½PtðNH 3 Þ 3 Cl þ , cis-diammine(pyridine)chloroplatinum(II) [cDPCP or "pyriplatin" (Fig. 1)] and related complexes display significant anticancer properties and a different spectrum of activity compared to conventional platinum-based drugs. These features render them attractive candidates for treating cisplatin-refractory patients if the potency could be raised to or beyond the level of that of cisplatin (4, 5, 7). Pyriplatin exhibits unique chemical and biological properties, forming monofunctional DNA adducts ( Fig. 1 and Fig. S1) that can inhibit transcription an...
Targeted anticancer prodrugs that can be controllably activated are highly desired for personalized precision medicine in cancer therapy. Such prodrugs with unique action modes are also promising to overcome drug resistance. Herein, we report coumaplatin, an oxaliplatin-based and photocaged Pt(IV) prodrug, to realize nuclear accumulation along with “on-demand” activation. This prodrug is based on a Pt(IV) complex that can be efficiently photoactivated via water oxidation without the requirement of a reducing agent. Coumaplatin accumulates very efficiently in the nucleoli, and upon photoactivation, this prodrug exhibits a level of photocytotoxicity up to 2 orders of magnitude higher than that of oxaliplatin. Unexpectedly, this prodrug presents strikingly enhanced tumor penetration ability and utilizes a distinct action mode to overcome drug resistance; i.e., coumaplatin but not oxaliplatin induces cell senescence, p53-independent cell death, and immunogenic cell death along with T cell activation. Our findings not only provide a novel strategy for the rational design of controllably activated and nucleolus-targeted Pt(IV) anticancer prodrugs but also demonstrate that accumulating conventional platinum drugs to the nucleus is a practical way to change its canonical mechanism of action and to achieve reduced resistance.
Theranostic nanomedicine is capable of diagnosis, therapy, and monitoring the delivery and distribution of drug molecules and has received growing interest. Herein, a self-monitored and self-delivered photosensitizer-doped FRET nanoparticle (NP) drug delivery system (DDS) is designed for this purpose. During preparation, a donor/acceptor pair of perylene and 5,10,15,20-tetro (4-pyridyl) porphyrin (H2TPyP) is co-doped into a chemotherapeutic anticancer drug curcumin (Cur) matrix. In the system, Cur works as a chemotherapeutic agent. In the meantime, the green fluorescence of Cur molecules is quenched (OFF) in the form of NPs and can be subsequently recovered (ON) upon release in tumor cells, which enables additional imaging and real-time self-monitoring capabilities. H2TPyP is employed as a photodynamic therapeutic drug, but it also emits efficient NIR fluorescence for diagnosis via FRET from perylene. By exploiting the emission characteristics of these two emitters, the combinatorial drugs provide a real-time dual-fluorescent imaging/tracking system in vitro and in vivo, and this has not been reported before in self-delivered DDS which simultaneously shows a high drug loading capacity (77.6%Cur). Overall, our carrier-free DDS is able to achieve chemotherapy (Cur), photodynamic therapy (H2TPyP), and real-time self-monitoring of the release and distribution of the nanomedicine (Cur and H2TPyP). More importantly, the as-prepared NPs show high cancer therapeutic efficiency both in vitro and in vivo. We expect that the present real-time self-monitored and self-delivered DDS with multiple-therapeutic and multiple-fluorescent ability will have broad applications in future cancer therapy.
Improved polyvinylpyrrolidone (PVP) microneedle arrays can be fabricated by adding cyclodextrin (CD) to form PVP–CD inclusion complexes.
We report the design, evaluation, and photoactivation mechanism of phorbiplatin, a platinum(IV) antitumor prodrug that can be controllably activated by red light. Phorbiplatin maintains its integrity without irradiation, but under irradiation with red light, the prodrug is quickly and efficiently activated, releasing oxaliplatin and PPA. The prodrug shows significant antitumor activity both in vitro and in vivo.
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