Long-term Photodynamic Therapy Research Articles

Chargeable persistent luminescence 3D-printed scaffolds: A stepwise tactic for osteosarcoma treatment

Osteosarcoma is the most frequent malignant primary bone tumor with a poor prognosis and remains a significant issue in clinics due to the unrepairable bone defect following surgery and the lingering tumor cells. Photodynamic therapy (PDT) with its non-invasive nature and spatiotemporally controllable feature exhibits specific therapeutic efficiency, but it is limited by phototoxicity caused by prolonged laser exposure. Herein, we design and engineer an irradiation-free bifunctional PDT scaffold (BG@SAO-RB) by integrating persistent luminescence material (SrAl2O4:Eu, Dy) and photosensitizer (rose bengal) into a 3D-printed bioactive glass scaffold for stepwise osteosarcoma elimination and bone defect repair. Owing to the design of a rechargeable internal light source, the constructed scaffolds with reactive oxygen species generation ability attain long-term and efficient PDT for osteosarcoma, leading to tumor cell killing and proliferative inhibition. The findings from tumor growth characteristics and pathological sections also confirm that BG@SAO-RB scaffolds achieve successful osteosarcoma ablation through long-term PDT in tumor-bearing nude mice. Notably, the as-designed scaffolds promote osteogenic differentiation of rat bone marrow mesenchymal stem cells and accelerate bone regeneration, which was evidenced by the improved radiological and histological manifestations. This work broadens the biomedical application of persistent luminescence materials and implicates an efficient treatment paradigm for osteosarcoma elimination and subsequent bone tissue regeneration.

Modern outlook for the use of photosensitizers with aggregation-induced emission in treatment of malignant tumors

Photodynamic therapy (PDT) is actively developing, becoming one of the important methods of non-invasive treatment of various oncological and infectious diseases. It is usually carried out using three main components: a photosensitizer, light, and oxygen. The key factors for the effective use of PDT are reactogenic oxygen species, which are produced during the oxidation of photosensitizers under the influence of light irradiation.
 To increase the production of reactogenic oxygen species, a technique was proposed for creating photosensitizers with aggregation-induced emission. At the present stage in oncology, the following PDT methods using photosensitizers with aggregation-induced emission are distinguished: PDT, absorbing near infrared radiation; enzyme- or glutathione-activated PDT; hypoxic PDT, and synergistic therapy.
 Compared to visible light, near infrared radiation (7001700 nm) has been shown to be more effective and safer due to reduced photodamage, less scattering, and deeper light penetration. The development of activated photosensitizers is an effective way to overcome the uncontrolled phototoxicity of photosensitizers during long-term PDT in vivo, providing controlled death of tumor cells. The oxygen concentration in tumor tissue varies depending on tumor progression, angiogenesis, metabolism, and metastasis. Therefore, the development of photosensitizers capable of effectively fluorescing under hypoxic conditions, including catalyzing intracellular substrates with the formation of oxygen and stimulating the production of reactogenic oxygen species through the type I mechanism, has become a potential solution to the problem of PDT of solid tumors.
 The therapeutic efficacy of a single PDT method, as well as most treatment methods in modern oncology, is limited. Therefore, a significant direction is the development of multifunctional treatment systems for synergistic therapy of tumors. Synergistic chemotherapy and PDT is an important area of treatment in oncology. The combination of PDT and immunotherapy is also a promising direction in the treatment of malignant neoplasms.
 There are obvious prospects for PDT in oncology not as a separate method of treatment, but as part of a complex multimodal treatment, including chemotherapy, radiation therapy, surgical treatment, and immunotherapy.

Bimetallic Ions Functionalized Metal-Organic-Framework Nanozyme for Tumor Microenvironment Regulating and Enhanced Photodynamic Therapy for Hypoxic Tumor.

Photodynamic therapy (PDT), as a light irradiation inducing reactive oxygen species (ROS) generation for cancer treatment, offers facile and promising solutions with respect to spatiotemporal control of ROS generation, and minimizes the systemic toxicity and side effects for highly precise tumor therapy. However, the PDT efficiency is often severely compromised by the complex tumor microenvironment (TME), such as the hypoxic condition and overexpressed antioxidants. Here, for the first time, a bimetallic ion-modified metal-organic framework nanozyme (Zr4+ -MOF-Ru3+ /Pt4+ -Ce6@HA, ZMRPC@HA) is designed. ZMRPC@HA with catalase (CAT) and glutathione oxidase (GSHOx) mimetic activities, can efficiently regulate TME by generation of O2 and deplete the GSH synergistically for enhancing the long-term PDT efficacy toward the hypoxic tumor. The in vitro cell inhibition and in vivo on tumor xenograft evaluations demonstrate the PDT strategy by using ZMRPC@HA can successfully inhibit the differentiation and proliferation of tumor cells under a 660nm laser irradiation in deep tissues. These findings open a new avenue for the design of multimetallic ions functionalized MOF-based nanozymes with multienzyme mimetic activities toward the antitumor and various other biological applications.

Metronomic Photodynamic Therapy Using an Implantable Electronic Device, a Preclinical Experiment for Introducing Phototherapy into Cancer Treatments in Internal Organs

Introduction: In a modern aging society, people expect high-quality cancer treatment but don't want to impair their quality of life. These trends made us imagine the needs of a novel cancer treatment system. We intend to develop a less invasive, low-cost cancer treatment system by using an implantable electronic device and introducing photodynamic therapy (PDT) into the treatment of malignancies in internal organs, including HBP area. Methods: We combined wirelessly powered fingernail-size LED chip, and tissue adhesive biomaterials to develop suture-free, tissue-adhesive, wirelessly powered LED devices. As a preclinical experiment, we investigated the anti-tumor effect of low-power and long-term photodynamic therapy, termed metronomic PDT, by using this device for the mouse cancer model. The device was implanted subcutaneously beneath intradermal tumors on the back of mice, and the mice could move freely in the cage placed on the antenna board that enables continuous illumination on the tumor. During the ten days of treatment, a photosensitizer (photofrin) was administered intravenously for two times. Results: The mice receiving mPDT showed significant growth suppression of the tumor when compared to the control mice. There was no adverse reaction in the surrounding normal tissues of the treatment group. Also, this experiment showed the effectiveness of green light, which has yet to be used clinically in PDT for the treatment of solid tumors. Conclusions: Metronomic PDT using implantable optoelectronic devices can be applied safely into the treatment of HBP malignancies as a low cost and less invasive local treatment method.

Irradiation-free photodynamic therapy in vivo induced by enhanced deep red afterglow within NIR-I bio-window

In situ precise anti-cancer therapeutics, such as imaging-guided photodynamic therapy (PDT), is one of the major efforts in reducing the mortality caused by tumor proliferation. Up to now, PDT can only be executed in hospital because of the restriction of relevant facilities and PDT specialists, e.g. lasers whose power density needs to be adjusted to a patient tolerable level on time. Therefore, an irradiation-free and long-term PDT is highly desirable in precision medicine, which may help for the realization of PDT at home for cancer patients. Herein, based on the facilitated tunneling process induced by Bi substitution in Cr doped zinc gallogermanate (ZGGO:Cr,Bi) deep red persistent luminescent nanoparticles (DRPLNPs) within NIR-I bio-window (650–950 nm), an irradiation-free PDT nanoplatform was constructed by loading zinc phthalocyanine (ZnPc) molecules into mesoporous silica coated on the surface of ZGGO:Cr,Bi DRPLNPS (ZGGO:Cr,Bi@mSiO2-ZnPc). It was demonstrated in vitro and in vivo that Bi substitution can effectively improve the afterglow intensity to such that the production of 1O2 is sufficient to have an apparent irradiation-free PDT. The inhibition factor of cancer growth two weeks after the injection of the nanocomposites was as high as ~80%. This work exhibits the interesting potential of the new generation of afterglow nanomaterials in precision medicine.

Accurate early prediction of tumour response to PDT using optical coherence angiography

Prediction of tumour treatment response may play a crucial role in therapy selection and optimization of its delivery parameters. Here we use optical coherence angiography (OCA) as a minimally-invasive, label-free, real-time bioimaging method to visualize normal and pathological perfused vessels and monitor treatment response following vascular-targeted photodynamic therapy (PDT). Preclinical results are reported in a convenient experimental model (CT-26 colon tumour inoculated in murine ear), enabling controlled PDT and post-treatment OCA monitoring. To accurately predict long-term treatment outcome, a robust and simple microvascular metric is proposed. It is based on perfused vessels density (PVD) at t = 24 hours post PDT, calculated for both tumour and peri-tumour regions. Histological validation in the examined experimental cohort (n = 31 animals) enabled further insight into the excellent predictive power of the derived early-response OCA microvascular metric. The results underscore the key role of peri-tumour microvasculature in determining the long-term PDT response.

Luminol Chemiluminescence Reports Photodynamic Therapy‐Generated Neutrophil Activity In Vivo and Serves as a Biomarker of Therapeutic Efficacy

Inflammatory cells, most especially neutrophils, can be a necessary component of the antitumor activity occurring after administration of photodynamic therapy. Generation of neutrophil responses has been suggested to be particularly important in instances when the delivered photodynamic therapy (PDT) dose is insufficient. In these cases, the release of neutrophil granules and engagement of antitumor immunity may play an important role in eliminating residual disease. Herein, we utilize invivo imaging of luminol chemiluminescence to noninvasively monitor neutrophil activation after PDT administration. Studies were performed in the AB12 murine model of mesothelioma, treated with Photofrin-PDT. Luminol-generated chemiluminescence increased transiently 1h after PDT, followed by a subsequent decrease at 4h after PDT. The production of luminol signal was not associated with the influx of Ly6G+ cells, but was related to oxidative burst, as an indicator of neutrophil function. Most importantly, greater levels of luminol chemiluminescence 1h after PDT were prognostic of a complete response at 90days after PDT. Taken together, this research supports an important role for early activity by Ly6G+ cells in the generation of long-term PDT responses in mesothelioma, and it points to luminol chemiluminescence as a potentially useful approach for preclinical monitoring of neutrophil activation by PDT.

Measurement of Cyanine Dye Photobleaching in Photosensitizer Cyanine Dye Conjugates Could Help in Optimizing Light Dosimetry for Improved Photodynamic Therapy of Cancer.

Photodynamic therapy (PDT) of cancer is dependent on three primary components: photosensitizer (PS), light and oxygen. Because these components are interdependent and vary during the dynamic process of PDT, assessing PDT efficacy may not be trivial. Therefore, it has become necessary to develop pre-treatment planning, on-line monitoring and dosimetry strategies during PDT, which become more critical for two or more chromophore systems, for example, PS-CD (Photosensitizer-Cyanine dye) conjugates developed in our laboratory for fluorescence-imaging and PDT of cancer. In this study, we observed a significant impact of variable light dosimetry; (i) high light fluence and fluence rate (light dose: 135 J/cm2, fluence rate: 75 mW/cm2) and (ii) low light fluence and fluence rate (128 J/cm2 and 14 mW/cm2 and 128 J/cm2 and 7 mW/cm2) in photobleaching of the individual chromophores of PS-CD conjugates and their long-term tumor response. The fluorescence at the near-infrared (NIR) region of the PS-NIR fluorophore conjugate was assessed intermittently via fluorescence imaging. The loss of fluorescence, photobleaching, caused by singlet oxygen from the PS was mapped continuously during PDT. The tumor responses (BALB/c mice bearing Colon26 tumors) were assessed after PDT by measuring tumor sizes daily. Our results showed distinctive photobleaching kinetics rates between the PS and CD. Interestingly, compared to higher light fluence, the tumors exposed at low light fluence showed reduced photobleaching and enhanced long-term PDT efficacy. The presence of NIR fluorophore in PS-CD conjugates provides an opportunity of fluorescence imaging and monitoring the photobleaching rate of the CD moiety for large and deeply seated tumors and assessing PDT tumor response in real-time.

Photosensitizer (PS)-cyanine dye (CD) conjugates: Impact of the linkers joining the PS and CD moieties and their orientation in tumor-uptake and photodynamic therapy (PDT)

To investigate the impact of linker(s) joining the photosensitizer HPPH [3-(1’-hexyloxy) ethyl-3-devinylpyropheophorbide-a] and the cyanine dye (CD) in tumor-imaging and photodynamic therapy (dual-function agents), a series of HPPH-CD conjugates were synthesized. The modifications were done in an attempt to minimize Forster Resonance Energy Transfer (FRET) between the two chromophores and maximize singlet oxygen production. Among the conjugates containing variable length of linkers, the HPPH-CD conjugate, in which the photosensitizer (PS) and the CD was joined by four Carbon [(CH2)4] units showed higher tumor uptake, improved tumor contrast and limited skin uptake in mice bearing Colon-26 (BALB/c) or U87 tumors in Nude mice. The bi-functional agents in which the HPPH was linked at the meta-position of phenyl-substituted CD 5, 6 and 7 showed longer tumor response (cure) than the corresponding para-substituted analogs 2, 3, and 4, which suggests that the orientation of the PS and CD moieties within the conjugate also makes a substantial difference in tumor-specificity. Compared to HPPH, the singlet oxygen yields of all the HPPH-CD conjugates were significantly low, and required a higher therapeutic dose to achieve the same in vivo response obtained by HPPH-PDT alone. However, conjugate 6 produced a higher singlet oxygen yield with reduced FRET and exhibited enhanced long-term PDT efficacy in mice bearing Colon-26 (BALB/c) and U87 tumors (nude) than its counterparts, including our lead compound (HPPH-CD), making it the most efficacious of the series. Thus, these conjugates bearing cyanine dye moiety (CD) provide an opportunity of imaging deeply seated tumors for fluorescence-guided surgery with an option of PDT.

Comparative Tumor Imaging and PDT Efficacy of HPPH Conjugated in the Mono- and Di-Forms to Various Polymethine Cyanine Dyes: Part - 2

Previous reports from our laboratory have shown that a bifunctional agent obtained by conjugating a photosensitizer (HPPH) to a cyanine dye (CD) can be used for fluorescence image-guided treatment of tumor by photodynamic therapy (PDT). However, the resulting HPPH-CD conjugate showed a significant difference between the tumor-imaging and therapeutic doses. It was demonstrated that the singlet oxygen (1O2*, a key cytotoxic agent in PDT) produced by the conjugate upon excitation of the HPPH moiety was partially quenched by the CD-moiety; this resulted in a reduced PDT response when compared to HPPH-PDT under similar treatment parameters. To improve the therapeutic potential of the conjugate, we synthesized a series of dual functional agents in which one or two HPPH moieties were separately conjugated to three different dyes (Cypate, modified IR820 or modified IR783). The newly synthesized conjugates were compared with our lead compound HPPH-CD in terms of photophysical properties, in vitro and in vivo PDT efficacy, tumor uptake and imaging potential. Among the analogs investigated, the conjugate, in which two HPPH moieties were linked to the modified IR820 produced enhanced tumor uptake and tumor contrast in both Colon 26 (a murine Colon carcinoma) and U87 (a human glioblastoma) cell lines. The long-term PDT efficacy (cure) of this conjugate in BALB/c mice, bearing Colon 26 tumors was also enhanced; however, its efficacy in Nude mice bearing U87 tumors was slightly reduced. It was also found that in all the conjugates the singlet oxygen generation and, consequently, PDT efficacy were compromised by a competing pathway, whereby an electronic excitation of HPPH, the energy donor, is deactivated through an electronic excitation energy transfer (Forster Resonance Energy Transfer, FRET) to the CD fluorophore, the energy acceptor, resulting in overall reduction of the singlet oxygen production. Conjugates with increased FRET showed reduced singlet oxygen production and PDT efficacy. Among the conjugates investigated, the bifunctional agent in which two HPPH moieties were linked to the benzoindole-based cyanine dye 11 showed superiority over the lead candidate 9 (mono HPPH-cyanine dye).

Predicting efficacy of photodynamic therapy by real-time FDG-PET in a mouse tumour model

Dynamic positron emission tomography (PET) combined with the constant infusion of 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) as a tracer permits real-time monitoring of systemic transient metabolic changes resulting from photodynamic therapy (PDT) in tumour bearing animals. The effect of PDT on tumour FDG uptake rates was evaluated using four different sulfonated phthalocyanine analogs as photosensitizers (PS) in combination with either continuous or fractionated illumination protocols. Mice bearing two EMT-6 tumours were infused with FDG to start PDT 30 min later. Dynamic images were acquired to produce FDG uptake over time for the treated and reference tumours. Practically all PDT protocols induced a reduction in the FDG uptake rates in the treated tumour during PDT, except for the zinc tetrasulfophthalocyanine, when using fractionated light, reflecting the low photodynamic efficacy of this PS. In general, the response to PDT was characterized by a rebound in the FDG uptake rate after illumination. A strong drop in FDG tumour uptake rates during PDT, followed by a strong rebound, together with short delay-to-response times, corresponded to optimal long-term tumour response outcomes. This dynamic FDG-PET protocol provides real-time observations to predict long-term PDT efficacy, while using fewer animals than conventional methods, thus making possible the rapid optimization of treatment parameters.

High and sustained efficacy after two sessions of topical 5-aminolaevulinic acid photodynamic therapy for basal cell carcinoma: a prospective, clinical and histological 10-year follow-up study

Prolonged follow-up data on topical photodynamic therapy (PDT) in basal cell carcinoma (BCC) are necessary for a full evaluation of its effect and for comparison with conventional treatment methods. To assess 10-year long-term PDT efficacy in primary and recurrent BCC and to evaluate clinical and histopathological factors which may be associated with treatment failure. We performed a longitudinal study on 60 histologically verified BCCs in 44 patients treated with curettage and one or two sessions of dimethylsulphoxide (DMSO)-supported topical 5-aminolaevulinic acid (ALA)-based PDT. Treated lesions were investigated by clinical and histopathological examination at regular intervals. The main outcomes were 10-year lesion complete response rate using a time-to-event analysis, histological treatment failure and cosmesis. Overall complete response rate for all lesions was 75% (95% confidence interval 64-87%); 60% after one and 87% after two treatment sessions. The response rate was 78% for primary lesions; 63% after one and 90% after two sessions. The cosmetic outcome was rated as good or excellent in 91-100% of evaluated cases. Treatment failure was documented in 15 (25%) of 60 lesions; clinical investigation identified 14 of them. All failures were noted within 3 years of treatment. Male gender, recurrent tumour and one treatment session were factors significantly associated with treatment failure. The only lesion larger than 2·0 cm relapsed. Two sessions of DMSO-supported topical ALA-PDT and curettage can provide long-term effective treatment results with favourable cosmetic outcome in primary, small BCC.

In Vitro Cellular Uptake and Dimerization of Signal Transducer and Activator of Transcription-3 (STAT3) Identify the Photosensitizing and Imaging-Potential of Isomeric Photosensitizers Derived from Chlorophyll-a and Bacteriochlorophyll-a

Among the photosensitizers investigated, both ring-D and ring-B reduced chlorins containing the m-iodobenzyloxyethyl group at position-3 and a carboxylic acid functionality at position-17(2) showed the highest uptake by tumor cells and light-dependent photoreaction that correlated with maximal tumor-imaging [positron emission tomography (PET) and fluorescence] and long-term photodynamic therapy (PDT) efficacy in BALB/c mice bearing Colon26 tumors. However, among the ring-D reduced compounds, the isomer containing the 1'-m-iobenzyloxyethyl group at position-3 was more effective than the corresponding 8-(1'-m-iodobenzyloxyethyl) derivative. All photosensitizers showed maximum uptake by tumor tissue 24 h after injection, and the tumors exposed with light at low fluence and fluence rates (128 J/cm(2), 14 mW/cm(2)) produced significantly enhanced tumor eradication than those exposed at higher fluence and fluence rate (135 J/cm(2), 75 mW/cm(2)). Interestingly, dose-dependent cellular uptake of the compounds and light-dependent STAT3 dimerization have emerged as sensitive rapid indicators for PDT efficacy in vitro and in vivo and could be used as in vitro/in vivo biomarkers for evaluating and optimizing the in vivo treatment parameters of the existing and new PDT candidates.

IL-6 potentiates tumor resistance to photodynamic therapy (PDT)

Photodynamic therapy (PDT) is an anticancer modality approved for the treatment of early disease and palliation of late stage disease. PDT of tumors results in the generation of an acute inflammatory response. The extent and duration of the inflammatory response is dependent upon the PDT regimen employed and is characterized by rapid induction of proinflammatory cytokines, such as IL-6, and activation and mobilization of innate immune cells. The importance of innate immune cells in long-term PDT control of tumor growth has been well defined. In contrast the role of IL-6 in long-term tumor control by PDT is unclear. Previous studies have shown that IL-6 can diminish or have no effect on PDT antitumor efficacy. In the current study we used mice deficient for IL-6, Il6(-/-) , to examine the role of IL-6 in activation of antitumor immunity and PDT efficacy by PDT regimens known to enhance antitumor immunity. Our studies have shown that elimination of IL-6 had no effect on innate cell mobilization into the treated tumor bed or tumor draining lymph node (TDLN) and did not affect primary antitumor T-cell activation by PDT. However, IL-6 does appear to negatively regulate the generation of antitumor immune memory and PDT efficacy against murine colon and mammary carcinoma models. The inhibition of PDT efficacy by IL-6 appears also to be related to regulation of Bax protein expression. Increased apoptosis was observed following treatment of tumors in Il6(-/-) mice 24 hours following PDT. The development of PDT regimens that enhance antitumor immunity has led to proposals for the use of PDT as an adjuvant treatment. However, our results show that the potential for PDT induced expression of IL-6 to enhance tumor survival following PDT must be considered.

Feasibility and safety of long-term photodynamic therapy (PDT) in the palliative treatment of patients with hilar cholangiocarcinoma

Background and AimPDT is an important palliative option for patients with unresectable extrahepatic cholangiocarcinoma (CC). However, the results published to date reported on studies with no more than 6 (mostly up to 4) PDT procedures. Furthermore, the clinical experience of PDT in combination with chemotherapy is limited. The purpose of this retrospective analysis was to evaluate the feasibility and safety of multiple (4 to 14) settings of PDT, combined with biliary drainage, and (in some cases) with chemotherapy.MethodsTen patients with unresectable extrahepatic CC were treated with biliary stenting and at least 4 PDT procedures in our department between 10/2005 and 08/2010.ResultsTen patients (male/female = 5/5), mean age 68.8 years (range, 54 - 81 years) who received at least 4 PDT procedures were analyzed. All patients underwent endoscopic biliary drainage. Nine patients received metallic stents and one patient a plastic stent. In 4 patients (40%) bilateral metal stenting (JoStent SelfX®) was performed. The mean number of PDT sessions was 7.9 ± 3.9 (range: 4 - 14). Eight patients had elevated bilirubin levels with a mean bilirubin at admission of 9.9 ± 11.3 mg/dL, which had decreased to an average minimum of 1.2 ± 0.9 mg/dL after 3 months. No severe toxicity was noted. Two patients received concomitant chemotherapy (GEMCIS as 1st line, GEMOX plus cetuximab as 2nd line). The median overall survival has not been reached, whereas the estimated survival of all patients was 47.6 months, 95% CI 25.9 - 48.1.ConclusionLong-term PDT in patients with extrahepatic CC is feasible and effective and is accompanied - at least in this cohort- by a survival time of more than 2 years.

Feasibility and safety of long-term photodynamic therapy (PDT) in the palliative treatment of patients with extrahepatic cholangiocarcinoma

Background and Aim: PDT is emerging as an important palliative option for patients with unresectable extrahepatic cholangiocarcinoma (CC). However, the results published to date reported on studies with no more than 6 (mostly up to 4) PDT procedures. Furthermore, the clinical experience of PDT in combination with chemotherapy is limited. The purpose of this retrospective analysis was to evaluate the feasibility and safety of multiple (4 to 14) settings of PDT, combined with biliary drainage, and (in some cases) with chemotherapy. Methods: Ten consecutive patients with unresectable extrahepatic CC were treated with biliary stenting and at least 4 PDT procedures in our department between 10/2005 and 08/2010. PDT was performed as described previously (1). Results: Ten patients (male/female=5/5), mean age 68.8 years (range, 54–81 years) which received at least 4 PDT procedures were analyzed. All patients underwent endoscopic biliary drainage. 9 patients received metallic stents and one patient a plastic stent. In 4 patients (40%) bilateral metal stenting (JoStent SelfX®) was performed as described previously (2). The mean number of PDT sessions was 7.9±3.9 (range: 4–14). Eight patients had elevated bilirubin levels with the mean bilirubin at admission of 9.9±11.3mg/dL, which decreased to an average minimum of 1.2±0.9mg/dL after 3 months. No severe toxicity was noted. Two patients received concomitant chemotherapy (GEMCIS as 1st line, GEMOX plus cetuximab as 2nd line). The median survival of all patients was 25.05 months. Conclusion: Long-term PDT in patients with extrahepatic CC is feasible and safe, and–at least in this cohort–accompanied by a median survival of more than two years.

Monitoring tumor response during photodynamic therapy using near-infrared photon-migration spectroscopy.

Benzoporphyrin-derivative (BPD)-monoacid-ring A photodynamic therapy (PDT) was performed on subcutaneous tumor implants in a rat ovarian cancer model. In order to assess PDT efficacy the tumor and normal tissue optical properties were measured noninvasively prior to and during PDT using frequency-domain photon migration (FDPM). FDPM data were used to quantify tissue absorption and reduced scattering properties (given by the parameters mu a and mu's, respectively) at four near-infrared (NIR) wavelengths (674, 811, 849 and 956 nm). Tissue physiologic properties, including the in vivo concentration of BPD, deoxy-hemoglobin (Hb), oxy-hemoglobin (HbO2), total hemoglobin (TotHb), water (H2O) and percent tissue hemoglobin oxygen saturation (%StO2), were calculated from optical property data. PDT efficacy was also determined from morphometric analysis of tumor necrosis in histologic specimens. All the measured tumor properties changed significantly during PDT. [Hb] increased by 9%, while [HbO2], [TotHb] and %StO2 decreased by 18, 7 and 12%, respectively. Using histologic data we show that long-term PDT efficacy is highly correlated to mean BPD concentration in tumor and PDT-induced acute changes in [HbO2], [TotHb] and %StO2 (correlation coefficients of 0.829, 0.817 and 0.953, respectively). Overall, our results indicate that NIR FDPM spectroscopy is able to quantify noninvasively and dynamically the PDT-induced physiological effects in vivo that are highly correlated with therapeutic efficacy.