Melanoma is the most aggressive type of skin cancer with the highest mortality rate, with surgery being the standard treatment. In this study, the effect of indocyanine green nanoemulsion in an animal model was evaluated for the treatment of cutaneous melanoma, using photothermal therapy. Different irradiation protocols, and nanoICG intratumoral and systemic delivery ways were tested. Macroscopic and histological analyses and Kaplan-Meier curves for animal survival are presented for comparison of the different investigated protocols.
Targeted photodynamic therapy (PDT) combined with image-guided surgical resection is a promising strategy for precision cancer treatment. Targeting the prostate-specific membrane antigen (PSMA) has drawn significant attention due to its marked overexpression in a variety of malignant tissues, most notably in prostate cancer. Recently, we reported the design of a pyropheophorbide-based long-circulating PSMA-targeted phototheranostic agent for multimodal PET/fluorescence imaging and potent PDT of prostate cancer. While this agent is effective in a subcutaneous mouse model, the non-optimal optical properties of pyropheophorbide (Qy absorption maximum at 671 nm) pose a limitation for treatment of deep-seated solid tumors. To further advance PSMA-targeted PDT and enable effective treatment to the deeper layers of tumor tissue, we developed a bacteriochlorophyll-based PSMA-targeted photosensitizer (BPP) which consists of three building blocks: 1) a urea-based PSMA-affinity ligand, 2) a peptide linker to prolong plasma circulation time, and 3) a bacteriochlorophyll photosensitizer for NIR fluorescence imaging (Qy absorption maximum at 750 nm). BPP demonstrated effective cell internalization as well as PDT activity in PSMA-expressing PC3-PIP cells. Furthermore, this agent possesses excellent targeting selectivity in vivo as demonstrated in a dual PSMA-positive and PSMA-negative subcutaneous tumor model. The peptide linker in BPP allowed for its long plasma circulation time (12.65 hours), which enabled its effective tumor accumulation. Overall, bright NIR fluorescence of BPP enables effective image guidance for surgical resection, while the combination of its superb targeting and strong PDT activity allows for potent and precise photodynamic treatment of deep-seated tumors.
Minimally-invasive alternatives for prostate cancer treatment are an unmet clinical need. We are currently conducting clinical trials using interstitial photothermal therapy (PTT) in focal (intermediate-risk) prostate cancer, targeting the largest (index) lesion, utilizing near-infrared (NIR) laser light that is delivered via one or more laser fibers placed interstitially to cover the target volume. This procedure is done using an interventional MRI suite where real-time MR thermometry is used to monitor treatment progression as a surrogate for tissue coagulation. We investigate here if photoacoustic imaging (PAI) could be used instead of MR thermometry to provide direct and higher specificity/sensitivity monitoring of the coagulation-front, particularly for the purpose of avoiding rectal wall damage. For this, we developed an in vivo canine PTT model and experiments were performed in 6 beagles with intact normal prostates, using similar approaches to those used in ongoing clinical trials. PTT also performed in vivo as well as in ex vivo porcine muscle. Initial results demonstrated the feasibility of both the PTT technique as well as an optimized monitoring platform. In ex vivo porcine muscle PAI demonstrated correlation with temperature (R2 = 0.66) that provided the impetus to move in vivo. However, due to noise and the relatively small changes in the PAI signal with coagulation this did not provide as much imaging depth or resolution as MR thermometry, the current gold standard. With newer PAI probes and deployment of the PAI light sources, it may be possible to increase the sensitivity of PAI for in vivo treatment monitoring. This work was supported by the Terry Fox Research Institute (Grant #1075).
Local disease control is a major challenge in pancreatic cancer treatment, because surgical resection of the primary tumor is only possible in a minority of patients and radiotherapy cannot be delivered in curative doses. Despite the promise of photothermal therapy (PTT) for focal ablation of pancreatic tumors, this approach remains underinvestigated. Using photothermal sensitizers in combination with laser light irradiation for PTT can result in more efficient conversion of light energy to heat and improved spatial confinement of thermal destruction to the tumor. Porphysomes are self-assembled nanoparticles composed mainly of pyropheophorbide-conjugated phospholipids, enabling the packing of ∼80,000 porphyrin photosensitizers per particle. The high-density porphyrin loading imparts enhanced photonic properties and enables high-payload tumor delivery. A patient-derived orthotopic pancreas xenograft model was used to evaluate the feasibility of porphysome-enhanced PTT for pancreatic cancer. Biodistribution and tumor accumulation were evaluated using fluorescence intensity measurements from homogenized tissues and imaging of excised organs. Tumor surface temperature was recorded using IR optical imaging during light irradiation to monitor treatment progress. Histological analyses were conducted to determine the extent of PTT thermal damage. These studies may provide insight into the influence of heat-sink effect on thermal therapy dosimetry for well-perfused pancreatic tumors.
Local disease control is a major problem in the treatment of pancreatic cancer, because curative-intent surgery is only
possible in a minority of patients, and radiotherapy cannot be delivered in curative doses. Despite the promise of
photothermal therapy (PTT) for ablation of pancreatic tumors, this approach remains under investigated. Using
photothermal sensitizers in combination with laser light for PTT can result in more efficient conversion of light energy
to heat, and confinement of thermal destruction to the tumor, thus sparing adjacent organs and vasculature. Porphyrins
have been previously employed as photosensitizers for PDT and PTT, however their incorporation in to “porphysomes”,
lipid-based nanoparticles each containing ~80,000 porphyrins through conjugation of pyropheophorbide to
phospholipids, carries two distinct advantages: 1) high-density porphyrin packing imparts the nanoparticles with
enhanced photonic properties for imaging and phototherapy; 2) the enhanced permeability and retention effect may be
exploited for optimal delivery of porphysomes to the tumor region thus high payload porphyrin delivery. The feasibility
of porphysome-enhanced PTT for pancreatic cancer treatment was investigated using a patient-derived orthotopic
pancreas xenograft tumor model. Uptake of porphysomes at the orthotopic tumor site was validated using ex vivo
fluorescence imaging of intact organs of interest. The accumulation of porphysomes in orthotopic tumor microstructure
was also confirmed by fluorescence imaging of excised tissue slices. PTT progress was monitored as changes in tumor
surface temperature using IR optical imaging. Histological analyses were conducted to examine microstructure changes
in tissue morphology, and the viability of remaining tumor tissues following exposure to heat. These studies may also
provide insight as to the contribution of heat sink in application of thermal therapies to highly vascularized pancreatic
tumors.
Photodynamic molecular beacon (PMB) is a novel photodynamic therapy (PDT) concept featuring the
precise control of the ability of photosensitizer (PS) to produce singlet oxygen in response to specific
cancer-associated biomarkers. It comprises a disease-specific linker, a PS and a singlet oxygen quencher so
that the PS's photodynamic toxicity is silenced until the linker interacts with a tumor-associated biomarker.
The development of PMB depends on two key factors. The first is the design of a suitable PS-quencher pair
to achieve an effective singlet oxygen quenching, minimizing phototoxicity of native PMB in non-targeted
(normal) cells. The second is the design of a suitable linker for the choice of target biomarker to achieve a
specific photodynamic activation, resulting in selective PDT efficacy in targeted (tumor) cells. These two
factors make PMB designs versatile and customizable. In this report, we will focus on the new directions
on PMB linker design utilizing two "on-and-off" activation mechanisms. The first one uses a "cleavable"
linker that is triggered by fibroblast activation protein or phospholipase. The second one uses an
"openable" linker that can hybridize with a tumor-specific mRNA.
Low density lipoproteins (LDL) have long been recognized as a potential delivery system for exogenous
agents. Imaging agents or drugs can be attached to LDL through surface loading, protein loading or core
loading methods. The LDL delivery system has received considerable attention particularly among cancer
biologists as it was observed that numerous cancers over-express the low density lipoprotein receptor
(LDLR). In this paper we investigate the utility of LDL to transport optical imaging contrast agents for
caner detection. The method of loading fluorophores into the core of LDL is attractive as it behaves like an
activatable contrast agent. Surface and protein labeled methods also prove to be effective strategies for
tracing LDL nanoparticle activity. The strengths and limitations of the LDL carrier system are discussed
and novel approaches for imaging cancer with LDL nanoparticles are highlighted.
Photodynamic therapy (PDT) involves the combined action of light, oxygen and a photosensitizer (PS). It offers
unique control in the PS's action because the key cytotoxic agent, singlet oxygen (1O2), is only produced in situ upon
irradiation. The 1O2 production can be controlled in three levels. The first level involves the judicious use of fiber optics
to selectively deliver light to disease tissues. The second level is to exert control over the PS's localization by selectively
delivering PS to cancer cells. The third level is to exert control of the PS's ability to generate 1O2 in responding to specific cancer biomarkers. Here, we present two PDT agents based on the latter two levels of 1O2 control. The first PDT agent "PPF" contains a PS (Pyro) and a tumor homing molecule (folate) and a peptide linker. PPF was found to be
selectively accumulated in cancer cells via folate receptor (FR) pathway. The second PDT agent "PPMMP7B" is a matrix
metalloproteinase-7 (MMP7)-triggered photodynamic molecular beacon (PMB) containing a PS (Pyro), a 1O2 quencher
(BHQ3) and a MMP7-cleavable peptide linker. Thus, the 1O2 production of PPMMP7B is highly sequence-specific and its photodynamic cytotoxicity is MMP7-dependent. Since these agents are designed to share functional modules (PS and peptide linker) and common cancer cell model (KB cells overexpress both FR and MMP7), it forms the basis for rational
design of receptor-targeted PMB for achieving a multi-level control of 1O2 production in cancer cells, which in term,
could provide a much higher level of PDT selectivity.
Access to the requested content is limited to institutions that have purchased or subscribe to SPIE eBooks.
You are receiving this notice because your organization may not have SPIE eBooks access.*
*Shibboleth/Open Athens users─please
sign in
to access your institution's subscriptions.
To obtain this item, you may purchase the complete book in print or electronic format on
SPIE.org.
INSTITUTIONAL Select your institution to access the SPIE Digital Library.
PERSONAL Sign in with your SPIE account to access your personal subscriptions or to use specific features such as save to my library, sign up for alerts, save searches, etc.