The achievement of nanoconstructs able to release therapeutic species in a controlled fashion and to be tracked in a biological environment is a major challenge in the burgeoning field of nanomedicine. Light is a powerful tool to fulfil these needs in a non-invasive way. By virtue of its easy manipulation in terms of energy, intensity, location and duration, light mimics an “optical syringe” that can activate fluorescence for imaging and stimulate a “burst” of therapeutics with superb spatiotemporal control, by using tailored photoresponsive systems. Besides their key role in the activation of therapeutic and imaging functionalities, photons represent powerful and “green” reactants for the facile synthesis of noble metal-based nanomaterials, which are suited for a variety of bio-applications due to their characteristic plasmonic absorption.
Photoactivatable Nanoconstructs for Biomedical Applications
Our current research aims at the design and fabrication of “smart” nanoconstructs able to release Nitric Oxide (NO), Singlet Oxygen (1O2) and “Heat” under the exclusive control of light stimuli. All these species represent intriguing “unconventional” therapeutics for anticancer and antibacterial applications and play a key role in the NO-stimulated, photodynamic and photothermal therapy. In our laboratory, we have been working on the design and fabrication of a number of nanoconstructs, including molecular hybrids, polymeric and mesoporous silica nanoparticles, quantum dots, hydrogels, thin films and differently shaped gold and silver nanostructures, that can be activated, synthesized or both by using Visible/Near Infrared light as suitable trigger and that also exhibit fluorescence, which is useful for bio-imaging. Particular emphasis is given to systems able to photogenerate simultaneously more than one therapeutic agent in view of multimodal therapeutic treatments exploiting additive/synergistic effects. For some representative and recent examples click on the boxes below.
Green light excitation of the rhodamine unit triggers its red-orange fluorescence, useful to monitor the preferential mitochondrial accumulation, and encourages the NO release from the nitroso appendage for cytotoxic effects on cancer cells.
Fine tuning of NO release by using blue light induces inhibition of the efflux pumps responsible for resistance of cancer cells, resulting in higher intracellular accumulation and enhanced cytotoxicity of the doxorubicin moiety.
A multicomponent supramolecular nanoassembly based on a cyclodextrin-branched polymer can be activated by two-photon excitation with NIR light at 740 nm. This allows the simultaneous activation of five distinct functionalities, that is, the generation of green, red, and blue fluorescence for bio-imaging, and the production of 1O2 and NO for bimodal anticancer therapeutic effects.
Pluronic copolymers self-assembling in core-shell nanoparticles and co-entrapping a photosensitizer and a caged Chlorambucil generate the cytotoxic 1O2 and liberate the free chemotherapeutic under the exclusive control of visible light, resulting in amplified mortality of cancer cell lines.
A “three bullet” nanoconstruct based on mesoporous silica nanoparticles for potential combined cancer photo-chemotherapy is able to generate 1O2 and NO under selective excitation with green and blue light, respectively and release the non-covalently entrapped anticancer DOX under physiological conditions.
Mesoporous silica nanoparticles release NO under light control and exploit the embedded carbon dots as fluorescent reporters for the NO liberated. These silica nanoparticles are also able to encapsulate the highly hydrophobic photosensitizer Temoporfin, preserving the fluorescent reporting function.
A multitasking photoresponsive supramolecular gel is easily achieved by the self-assembling of two polymeric components and two chromo-fluorogenic centers. Excitation with visible light results in the red and green fluorescence emission of the gel and in its capability to generate 1O2 and NO as bactericidal agents.
A microemulsion co-solubilizing a photosensitizer and a NO photodonor in the oily phase can be selectively excited with visible light stimuli of different wavelength resulting in the photogeneration of the cytotoxic 1O2 and NO, red and green fluorescence emission and amplified photobactericidal action.
A NO photoreleaser with a fluorescent reporter has been integrated in the biocompatible PLGA resulting in a photoactivatable polymeric film. The NO release process can be activated by sunlight and can be followed in real time by the intense blue fluorescence the optical reporter. Once photogenerated, the NO radical promptly diffuses out of the polymeric matrix to reach biological target and induces excellent bactericidal activity.
The same principle shown left is extended to soft contact lens. The fluorescent reporting functionality, which activates concomitantly to the NO photorelease, allows the easy monitoring of the NO delivery in real time and confirms the working of the doped lens under daylight exposure. The NO photoreleasing lens are well-tolerated in both dark and light conditions by corneal cells while being able to induce good bacteria growth inhibition under visible light irradiation.
Noble Metal Nanostructures
Water-dispersible Au nanotriangles and nanoflowers with NIR localized surface plasmon absorption are obtained by a simple “green” procedure based on the NO generated by visible light irradiation of a tailored cyclodextrin-branched polymer. Excitation of these nanostructures with 808 nm NIR light induces photothermal effects useful for cancer cell death and enzymatic reaction activation.
Water-dispersible Ag, Au and Au@Ag core-shell nanoparticles are rapidly and effectively obtained through the very fast generation of the highly reducing ketyl radical upon light irradiation of a biocompatible dextran functionalized with benzophenone. The resulting nanoparticles shows excellent antibacterial action and remarkable photothermal activity.