Tumoricidal photodynamic (PDT) and photothermal (PTT) therapies harness light to eliminate cancer cells with spatiotemporal precision by either generating reactive oxygen species or increasing ...temperature. Great strides have been made in understanding biological effects of PDT and PTT at the cellular, vascular and tumor microenvironmental levels, as well as translating both modalities in the clinic. Emerging evidence suggests that PDT and PTT may synergize due to their different mechanisms of action, and their nonoverlapping toxicity profiles make such combination potentially efficacious. Moreover, PDT/PTT combinations have gained momentum in recent years due to the development of multimodal nanoplatforms that simultaneously incorporate photodynamically- and photothermally active agents. In this review, we discuss how combining PDT and PTT can address the limitations of each modality alone and enhance treatment safety and efficacy. We provide an overview of recent literature featuring dual PDT/PTT nanoparticles and analyze the strengths and limitations of various nanoparticle design strategies. We also detail how treatment sequence and dose may affect cellular states, tumor pathophysiology and drug delivery, ultimately shaping the treatment response. Lastly, we analyze common experimental design pitfalls that complicate preclinical assessment of PDT/PTT combinations and propose rational guidelines to elucidate the mechanisms underlying PDT/PTT interactions.
In the spring of 1871, Ralph Waldo Emerson boarded a train in
Concord, Massachusetts, bound for a month-and-a-half-long tour of
California-an interlude that became one of the highlights of his
life. ...On their journey across the American West, he and his
companions would take in breathtaking vistas in the Rockies and
along the Pacific Coast, speak with a young John Muir in the
Yosemite Valley, stop off in Salt Lake City for a meeting with
Brigham Young, and encounter a diversity of communities and
cultures that would challenge their Yankee prejudices.
Based on original research employing newly discovered documents,
The California Days of Ralph Waldo Emerson maps the public
story of this group's travels onto the private story of Emerson's
final years, as aphasia set in and increasingly robbed him of his
words. Engaging and compelling, this travelogue makes it clear that
Emerson was still capable of wonder, surprise, and friendship,
debunking the presumed darkness of his last decade.
Photodynamic therapy (PDT) uses light-activated drugs to treat diseases ranging from cancer to age-related macular degeneration and antibiotic-resistant infections. This paper reviews the current ...status of PDT with an emphasis on the contributions of physics, biophysics and technology, and the challenges remaining in the optimization and adoption of this treatment modality. A theme of the review is the complexity of PDT dosimetry due to the dynamic nature of the three essential components -- light, photosensitizer and oxygen. Considerable progress has been made in understanding the problem and in developing instruments to measure all three, so that optimization of individual PDT treatments is becoming a feasible target. The final section of the review introduces some new frontiers of research including low dose rate (metronomic) PDT, two-photon PDT, activatable PDT molecular beacons and nanoparticle-based PDT.
Medical devices face many hurdles before they enter routine clinical practice to address unmet clinical needs. This is also the case for biomedical optical spectroscopy and imaging systems that are ...used here to illustrate the opportunities and challenges involved. Following initial concept, stages in clinical translation include instrument development, preclinical testing, clinical prototyping, clinical trials, prototype-to-product conversion, regulatory approval, commercialization, and finally clinical adoption and dissemination, all in the face of potentially competing technologies. Optical technologies face additional challenges from their being extremely diverse, often targeting entirely different diseases and having orders-of-magnitude differences in resolution and tissue penetration. However, these technologies can potentially address a wide variety of unmet clinical needs since they provide rich intrinsic biochemical and structural information, have high sensitivity and specificity for disease detection and localization, and are practical, safe (minimally invasive, nonionizing), and relatively affordable.
Photodynamic therapy (PDT) uses photosensitizers and visible light in combination with molecular oxygen to produce reactive oxygen species (ROS) that kill malignant cells by apoptosis and/or ...necrosis, shut down the tumor microvasculature and stimulate the host immune system. The excited singlet state of oxygen (
O
) is recognized to be the main cytotoxic ROS generated during PDT for the majority of photosensitizers used clinically and for many investigational new agents, so that maximizing its production within tumor cells and tissues can improve the therapeutic response, and several emerging and novel approaches for this are summarized. Quantitative techniques for
O
production measurement during photosensitization are also of immense importance of value for both preclinical research and future clinical practice. In this review, emerging strategies for enhanced photosensitized
O
generation are introduced, while recent advances in direct detection and imaging of
O
luminescence are summarized. In addition, the correlation between cumulative
O
luminescence and PDT efficiency will be highlighted. Meanwhile, the validation of
O
luminescence dosimetry for PDT application is also considered. This review concludes with a discussion on future demands of
O
luminescence detection for PDT dosimetry, with particular emphasis on clinical translation. Eye-catching color image for graphical abstract.
Photodynamic therapy (PDT) is generally based on the generation of highly reactive singlet oxygen (1O2) through interactions of photosensitizer, light, and oxygen (3O2). These three components are ...highly interdependent and dynamic, resulting in variable temporal and spatial 1O2 dose deposition. Robust dosimetry that accounts for this complexity could improve treatment outcomes. Although the 1270 nm luminescence emission from 1O2 provides a direct and predictive PDT dose metric, it may not be clinically practical. We used 1O2 luminescence (or singlet oxygen luminescence (SOL)) as a gold-standard metric to evaluate potentially more clinically feasible dosimetry based on photosensitizer bleaching. We performed in vitro dose-response studies with simultaneous SOL and photosensitizer fluorescence measurements under various conditions, including variable 3O2, using the photosensitizer meta-tetra(hydroxyphenyl)chlorin (mTHPC). The results show that SOL was always predictive of cytotoxicity and immune to PDT's complex dynamics, whereas photobleaching-based dosimetry failed under hypoxic conditions. However, we identified a previously unreported 613 nm emission from mTHPC that indicates critically low 3O2 levels and can be used to salvage photobleaching-based dosimetry. These studies improve our understanding of PDT processes, demonstrate that SOL is a valuable gold-standard dose metric, and show that when used judiciously, photobleaching can serve as a surrogate for 1O2 dose.
Converting nanoparticles or monomeric compounds into larger supramolecular structures by endogenous or external stimuli is increasingly popular because these materials are useful for imaging and ...treating diseases. However, conversion of microstructures to nanostructures is less common. Here, we show the conversion of microbubbles to nanoparticles using low-frequency ultrasound. The microbubble consists of a bacteriochlorophyll-lipid shell around a perfluoropropane gas. The encapsulated gas provides ultrasound imaging contrast and the porphyrins in the shell confer photoacoustic and fluorescent properties. On exposure to ultrasound, the microbubbles burst and form smaller nanoparticles that possess the same optical properties as the original microbubble. We show that this conversion is possible in tumour-bearing mice and could be validated using photoacoustic imaging. With this conversion, our microbubble can potentially be used to bypass the enhanced permeability and retention effect when delivering drugs to tumours.
X-ray and optical technologies are the two central pillars for human imaging and therapy. The strengths of x-rays are deep tissue penetration, effective cytotoxicity, and the ability to image with ...robust projection and computed-tomography methods. The major limitations of x-ray use are the lack of molecular specificity and the carcinogenic risk. In comparison, optical interactions with tissue are strongly scatter dominated, leading to limited tissue penetration, making imaging and therapy largely restricted to superficial or endoscopically directed tissues. However, optical photon energies are comparable with molecular energy levels, thereby providing the strength of intrinsic molecular specificity. Additionally, optical technologies are highly advanced and diversified, being ubiquitously used throughout medicine as the single largest technology sector. Both have dominant spatial localization value, achieved with optical surface scanning or x-ray internal visualization, where one often is used with the other. Therapeutic delivery can also be enhanced by their synergy, where radio-optical and optical-radio interactions can inform about dose or amplify the clinical therapeutic value. An emerging trend is the integration of nanoparticles to serve as molecular intermediates or energy transducers for imaging and therapy, requiring careful design for the interaction either by scintillation or Cherenkov light, and the nanoscale design is impacted by the choices of optical interaction mechanism. The enhancement of optical molecular sensing or sensitization of tissue using x-rays as the energy source is an important emerging field combining x-ray tissue penetration in radiation oncology with the molecular specificity and packaging of optical probes or molecular localization. The ways in which x-rays can enable optical procedures, or optics can enable x-ray procedures, provide a range of new opportunities in both diagnostic and therapeutic medicine. Taken together, these two technologies form the basis for the vast majority of diagnostics and therapeutics in use in clinical medicine.
Modern cancer diagnosis requires histological, molecular, and genomic tumor analyses. Tumor sampling is often achieved using a targeted needle biopsy approach. Targeting errors and cancer ...heterogeneity causing inaccurate sampling are important limitations of this blind technique leading to non-diagnostic or poor quality samples, and the need for repeated biopsies pose elevated patient risk. An optical technology that can analyze the molecular nature of the tissue prior to harvesting could improve cancer targeting and mitigate patient risk. Here we report on the design, development, and validation of an in situ intraoperative, label-free, cancer detection system based on high wavenumber Raman spectroscopy. This optical detection device was engineered into a commercially available biopsy system allowing tumor analysis prior to tissue harvesting without disrupting workflow. Using a dual validation approach we show that high wavenumber Raman spectroscopy can detect human dense cancer with >60% cancer cells in situ during surgery with a sensitivity and specificity of 80% and 90%, respectively. We also demonstrate for the first time the use of this system in a swine brain biopsy model. These studies set the stage for the clinical translation of this optical molecular imaging method for high yield and safe targeted biopsy.
Singlet oxygen is a primary cytotoxic agent in photodynamic therapy. We show that CeF3 nanoparticles, pure as well as conjugated through electrostatic interaction with the photosensitizer ...verteporfin, are able to generate singlet oxygen as a result of UV light and 8 keV X-ray irradiation. The X-ray stimulated singlet oxygen quantum yield was determined to be 0.79 ± 0.05 for the conjugate with 31 verteporfin molecules per CeF3 nanoparticle, the highest conjugation level used. From this result we estimate the singlet oxygen dose generated from CeF3-verteporfin conjugates for a therapeutic dose of 60 Gy of ionizing radiation at energies of 6 MeV and 30 keV to be (1.2 ± 0.7) × 10(8) and (2.0 ± 0.1) × 10(9) singlet oxygen molecules per cell, respectively. These are comparable with cytotoxic doses of 5 × 10(7)-2 × 10(9) singlet oxygen molecules per cell reported in the literature for photodynamic therapy using light activation. We confirmed that the CeF3-VP conjugates enhanced cell killing with 6 MeV radiation. This work confirms the feasibility of using X- or γ- ray activated nanoparticle-photosensitizer conjugates, either to supplement the radiation treatment of cancer, or as an independent treatment modality.
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