Dmitri O. Lapotko

Plasmonic Nanobubbles as Transient Vapor Nanobubbles Generated Around Plasmonic Nanoparticles

We have used short laser pulses to generate transient vapor nanobubbles around plasmonic nanoparticles. The photothermal, mechanical, and optical properties of such bubbles were found to be different from those of plasmonic nanoparticle and vapor bubbles, as well. This phenomenon was considered as a new complex nanosystem-plasmonic nanobubble (PNB). Mechanical and optical scattering properties of PNB depended upon the nanoparticle surface and heat capacity, clusterization state, and the optical pulse length. The generation of the PNB required much higher laser pulse fluence thresholds than the explosive boiling level and was characterized by the relatively high lower threshold of the minimal size (lifetime) of PNB. Optical scattering by PNB and its diameter (measured as the lifetime) has been varied with the fluence of laser pulse, and this has demonstrated the tunable nature of PNB.

Optical excitation and detection of vapor bubbles around plasmonic nanoparticles

Laser-induced generation of the vapor bubbles in water around plasmonic nanoparticles was experimentally studied with optical scattering methods. Nanoparticle-generated bubbles temporally and spatially localize laser-induced thermal field and also amplify optical scattering relatively to that of gold nanoparticles. Bubble lifetimes and threshold fluencies were determined as functions of the laser (pulse duration, fluence, inter-pulse interval), nanoparticle (size, shape, aggregation state) and sample chamber parameters so to optimize bubble generation around plasmonic nanoparticles. Nanoparticle-generated bubbles are suggested as nano-scaled optical sensors and sources of localized thermal and mechanical impact.

Tunable plasmonic nanobubbles for cell theranostics

Combining diagnostic and therapeutic processes into one (theranostics) and improving their selectivity to the cellular level may offer significant benefits in various research and disease systems and currently is not supported with efficient methods and agents. We have developed a novel method based on the gold nanoparticle-generated transient photothermal vapor nanobubbles, that we refer to as plasmonic nanobubbles (PNB). After delivery and clusterization of the gold nanoparticles (NP) to the target cells the intracellular PNBs were optically generated and controlled through the laser fluence. The PNB action was tuned in individual living cells from non-invasive high-sensitive imaging at lower fluence to disruption of the cellular membrane at higher fluence. We have achieved non-invasive 50-fold amplification of the optical scattering amplitude with the PNBs (relative to that of NPs), selective mechanical and fast damage to specific cells with bigger PNBs, and optical guidance of the damage through the damage-specific signals of the bubbles. Thus the PNBs acted as tunable theranostic agents at the cellular level and in one process that have supported diagnosis, therapy and guidance of the therapy.

Photothermal imaging of nanoparticles and cells

This review summarizes the findings of recent applications of time-domain far-field photothermal (PT) technique to the detection and imaging of nanoscale absorbing particles. This two-beam (pump-probe) technique is based on time-resolved PT visualization of laser-induced thermal effects around nanoparticles. Imaging is accomplished, after an adjustable time delay after the pump laser pulse, with a second probe beam that senses the nanotarget. Using a tunable optical parametric oscillator laser (wavelength, 420 to 570 nm; energy, 0.1-300 /spl mu/J; pulse width, 8 ns) as the pump laser and a Raman shifter (639 nm, 10 nJ, 13 ns) as the probe laser, with a tunable delay of 0 to 5 000 ns of the probe pulse relative to the pump pulse, this approach has demonstrated the capability to visualize nanoscale gold particles (2 to 250 nm) alone and in cells, liposomes (30 to 90 nm), neutral red-stained particles (30 to 500 nm), and polystyrene beads. Different applications of the time-resolved PT technique are discussed, including imaging of absorbing cellular nanostructures and optimization of selective killing of cancer cells and bacteria.

The in vivo performance of plasmonic nanobubbles as cell theranostic agents in zebrafish hosting prostate cancer xenografts

Cell theranostics is a new approach that unites diagnosis, therapy and confirmation (guidance) of the results of therapy in one single process at cell level, thus principally improving both the rapidity and precision of treatment. The ideal theranostic agent will support all three of the above functions in vivo with cellular resolution, allowing individual assessment of disease state and the elimination of diseased cells while leaving healthy cells intact. We have developed and evaluated plasmonic nanobubbles (PNBs) as an in vivo tunable theranostic cellular agent in zebrafish hosting prostate cancer xenografts. PNBs were selectively generated around gold nanoparticles in cancer cells in the zebrafish with short single laser pulses. By varying the energy of the laser pulse, we dynamically tuned the PNB size in a theranostic sequence of two PNBs: an initial small PNB detected a cancer cell through optical scattering, followed by a second bigger PNB, which mechanically ablated this cell without damage to surrounding tissue, while its optical scattering confirmed the destruction of the cell. Thus PNBs supported the diagnosis and guided ablation of individual human cancer cells in a living organism without damage to the host.

Plasmonic nanobubble-enhanced endosomal escape processes for selective and guided intracellular delivery of chemotherapy to drug-resistant cancer cells

Cancer chemotherapies suffer from multi drug resistance, high non-specific toxicity and heterogeneity of tumors. We report a method of plasmonic nanobubble-enhanced endosomal escape (PNBEE) for the selective, fast and guided intracellular delivery of drugs through a self-assembly by cancer cells of separately targeted gold nanoparticles and encapsulated drug (Doxil). The co-localized with Doxil plasmonic nanobubbles optically generated in cancer cells released the drug into the cytoplasm thus increasing the therapeutic efficacy against these drug-resistant cells by 31-fold, reducing drug dose by 20-fold, the treatment time by 3-fold and the non-specific toxicity by 10-fold compared to standard treatment. Thus the PNBEE mechanism provided selective, safe and efficient intracellular drug delivery in heterogeneous environment opening new opportunities for drug therapies.

LANTCET: elimination of solid tumor cells with photothermal bubbles generated around clusters of gold nanoparticles

BACKGROUND We have developed a method, termed laser-activated nano-thermolysis as a cell elimination technology (LANTCET), for the selective detection and destruction of individual tumor cells by the generation of intracellular photothermal bubbles around clusters of gold nanoparticles. METHOD Bare nanoparticles and their conjugates to C225 tumor-specific monoclonal antibodies were applied in vitro to C225-positive squamous carcinoma cells and in vivo to an experimental tumor in a rat in order to form intracellular clusters of nanoparticles. RESULTS Single 10 ns laser pulses generated intracellular photothermal microbubbles at a near-infrared and visible wavelengths. The cells with the clusters yielded an almost 100-fold decrease in the laser fluence threshold for bubble generation and cell damage relative to that for the cells without clusters. Cell damage had a mechanical origin and single cell selectivity. Three LANTCET processes (cell detection, damage and optical guidance) were realized as a microsecond sequence and with the one device.

Optically guided controlled release from liposomes with tunable plasmonic nanobubbles.

A new method of optically guided controlled release was experimentally evaluated with liposomes containing a molecular load and gold nanoparticles (NPs). NPs were exposed to short laser pulses to induce transient vapor bubbles around the NPs, plasmonic nanobubbles, in order to disrupt the liposome and eject its molecular contents. The release efficacy was tuned by varying the lifetime and size of the nanobubble with the fluence of the laser pulse. Optical scattering by nanobubbles correlated to the molecular release and was used to guide the release. The release of two fluorescent proteins from individual liposomes has been directly monitored by fluorescence microscopy, while the generation of the plasmonic nanobubbles was imaged and measured with optical scattering techniques. Plasmonic nanobubble-induced release was found to be a mechanical, nonthermal process that requires a single laser pulse and ejects the liposome contents within a millisecond timescale without damage to the molecular cargo and that can be controlled through the fluence of laser pulse.

On-demand intracellular amplification of chemoradiation with cancer-specific plasmonic nanobubbles

Chemoradiation-resistant cancers limit treatment efficacy and safety. We show here the cancer cell–specific, on-demand intracellular amplification of chemotherapy and chemoradiation therapy via gold nanoparticle– and laser pulse–induced mechanical intracellular impact. Cancer aggressiveness promotes the clustering of drug nanocarriers and gold nanoparticles in cancer cells. This cluster, upon exposure to a laser pulse, generates a plasmonic nanobubble, the mechanical explosion that destroys the host cancer cell or ejects the drug into its cytoplasm by disrupting the liposome and endosome. The same cluster locally amplifies external X-rays. Intracellular synergy of the mechanical impact of plasmonic nanobubble, ejected drug and amplified X-rays improves the efficacy of standard chemoradiation in resistant and aggressive head and neck cancer by 100-fold in vitro and 17-fold in vivo, reduces the effective entry doses of drugs and X-rays to 2–6% of their clinical doses and efficiently spares normal cells. The developed quadrapeutics technology combines four clinically validated components and transforms a standard macrotherapy into an intracellular on-demand theranostic microtreatment with radically amplified therapeutic efficacy and specificity.

Plasmonic Nanobubbles Enhance Efficacy and Selectivity of Chemotherapy Against Drug‐Resistant Cancer Cells

Oral cavity squamous cell carcinoma (OCSCC) is one of the most prevalent malignancies affecting patients worldwide.[1] Advanced OCSCCs are at high risk for local recurrence and are associated with poor prognosis.[2] The major reasons for this are 1) incomplete removal of cancer cells by surgery, especially when complicated by micro metastasis and co-localization of cancer cells with functionally or cosmetically important structures; 2) multi-drug resistance of cancer cells, and 3) acute and long-term toxicities of radio- and chemo-therapies. Therefore, new treatment strategies are needed to provide cell level selectivity of cancer treatment and high efficacy against drug-resistant cells for OCSCC and other superficial cancers.