Sequential Photodynamic Therapy Research Articles

Nanoparticles Yield Increased Drug Uptake and Therapeutic Efficacy upon Sequential Near-Infrared Irradiation.

Nanoparticles offer great opportunities for precision medicine. However, the use of nanoparticles as smart photosensitizers that target tumor biomarkers and are responsive to the tumor microenvironment has yet to be explored. Herein, prostate cancer (PCa)-selective theranostic gold nanoparticles (AuNPs) for precise cancer imaging and therapy are developed. Silicon phthalocyanine, Pc158, was synthesized and deactivated by conjugating it to AuNPs via a biocleavable linker. In vitro and in vivo, the targeted AuNPs show excellent selectivity for PSMA-positive tumor cells. Triggered release of the therapeutic, Pc158, followed by sequential photodynamic therapy (PDT) results in significant inhibition of tumor growth. Further, we demonstrate that multiple sequential PDT greatly enhances nanoparticle uptake and therapeutic efficacy. PSMA is highly expressed in the neovasculature of most other solid tumors in humans, as well as PCa, making this approach of great practical interest for precision PDT in a wide range of cancers.

Sequential PDT and PTT Using Dual-Modal Single-Walled Carbon Nanohorns Synergistically Promote Systemic Immune Responses against Tumor Metastasis and Relapse.

Immune responses stimulated by photodynamic therapy (PDT) and photothermal therapy (PTT) are a promising strategy for the treatment of advanced cancer. However, the antitumor efficacy by PDT or PTT alone is less potent and unsustainable against cancer metastasis and relapse. In this study, Gd3+ and chlorin e6 loaded single‐walled carbon nanohorns (Gd‐Ce6@SWNHs) are developed, and it is demonstrated that they are a strong immune adjuvant, and have high tumor targeting and penetration efficiency. Then, three in vivo mouse cancer models are established, and it is found that sequential PDT and PTT using Gd‐Ce6@SWNHs synergistically promotes systemic antitumor immune responses, where PTT stimulates dendritic cells (DCs) to secrete IL‐6 and TNF‐α, while PDT triggers upregulation of IFN‐γ and CD80. Moreover, migration of Gd‐Ce6@SWNHs from the targeted tumors to tumor‐draining lymph nodes sustainably activates the DCs to generate a durable immune response, which eventually eliminates the distant metastases without using additional therapeutics. Gd‐Ce6@SWNHs intervened phototherapies also generate durable and long‐term memory immune responses to tolerate and prevent cancer rechallenge. Therefore, this study demonstrates that sequential PDT and PTT using Gd‐Ce6@SWNHs under moderate conditions elicits cooperative and long‐lasting antitumor immune responses, which are promising for the treatment of patients with advanced metastatic cancers.

Sequential Photodynamic Therapy with Phthalocyanine Encapsulated Chitosan-Tripolyphosphate Nanoparticles and Flucytosine Treatment against Candida tropicalis.

Antibiotic resistance has become a crisis. Candida tropicalis (C. tropicalis) is one of the most highly virulent and drug-resistant pathogens. An alternative antimicrobial therapy to eradicate C. tropicalis effectively, without the risk of developing drug-resistance, is needed. Photodynamic therapy (PDT) is an alternative therapy that does not carry the risk of undesired drug resistance. To target the pathogens and to enhance the cellular penetration of the applied photosensitizer, we fabricated cationic chitosan/tripolyphosphate nanoparticles to encapsulate phthalocyanine. Our strategy promotes the uptake of phthalocyanine four-fold. This enhanced PDT can effectively inhibit planktonic C. tropicalis, such that only ~20% of C. tropicalis in the test survived; but it has a limited ability to inhibit adherent C. tropicalis. Further tests with adherent C. tropicalis indicated that sequential treatment with PDT and flucytosine significantly eliminates pseudohyphae and yeast-like C. tropicalis cells. The cell viability is only ~10% after this sequential treatment. This study provides evidence of an effective therapy against drug resistant C. tropicalis, and this strategy can be potentially applied to other pathogens.

Theranostic Liposomes with Hypoxia-Activated Prodrug to Effectively Destruct Hypoxic Tumors Post-Photodynamic Therapy.

Photodynamic therapy (PDT), a noninvasive cancer therapeutic method triggered by light, would lead to severe tumor hypoxia after treatment. Utilizing a hypoxia-activated prodrug, AQ4N, which only shows toxicity to cancer cells under hypoxic environment, herein, a multipurpose liposome is prepared by encapsulating hydrophilic AQ4N and hydrophobic hexadecylamine conjugated chlorin e6 (hCe6), a photosensitizer, into its aqueous cavity and hydrophobic bilayer, respectively. After chelating a 64Cu isotope with Ce6, the obtained AQ4N-64Cu-hCe6-liposome is demonstrated to be an effective imaging probe for in vivo positron emission tomography, which together with in vivo fluorescence and photoacoustic imaging uncovers efficient passive homing of those liposomes after intravenous injection. After being irradiated with the 660 nm light-emitting diode light, the tumor bearing mice with injection of AQ4N-hCe6-liposome show severe tumor hypoxia, which in turn would trigger activation of AQ4N, and finally contributes to remarkably improved cancer treatment outcomes via sequential PDT and hypoxia-activated chemotherapy. This work highlights a liposome-based theranostic nanomedicine that could utilize tumor hypoxia, a side effect of PDT, to trigger chemotherapy, resulting in greatly improved efficacy compared to conventional cancer PDT.

Promotion of Proapoptotic Signals by Lysosomal Photodamage: Mechanistic Aspects and Influence of Autophagy.

Prior studies demonstrated that a low level (LD10-15 ) of lysosomal photodamage can sensitize cells to the apoptotic death that results from subsequent mitochondrial photodamage. We have proposed that this process occurs via a calpain-catalyzed cleavage of the autophagy-associated protein ATG5 to form a proapoptotic fragment. In this report, we provide evidence for the postulated ATG5 cleavage and show that the sequential photodynamic therapy (PDT) protocol can also partly overcome the adverse effect of hypoxia on the initiation of apoptosis. While autophagy can offer cytoprotection after mitochondrial photodamage, this does not appear to apply when lysosomes are the target. This may account for the ability of very low PDT doses directed at lysosomes to evoke ATG5 cleavage. The resulting proapoptotic effect overcomes intrinsic cytoprotection from mitochondrial photodamage along with a further stimulation of phototoxicity.

Treatment of basal cell carcinoma with sequential photodynamic therapy and imiquimod cream may improve long-term patient outcomes

Treatment of basal cell carcinoma with sequential photodynamic therapy and imiquimod cream may improve long-term patient outcomes

Can Intravitreal Tissue Plasminogen Activator and SF6 Gas Facilitate Management of Macular Degeneration with Photodynamic Therapy?

To describe the safety and efficacy of intravitreal tissue plasminogen activator (tPA) and sulfur hexafluoride (SF6) gas with sequential photodynamic therapy (PDT) in the management of submacular hemorrhage (SMH) associated with macular degeneration (MD). Consecutive case series of five patients presenting with acute SMH from neovascular MD between May 2004 and January 2006 in a UK Eye Centre. Duration of visual loss was less than 7 weeks. Treatment involved intravitreal injections of tPA, SF6 gas to achieve pneumatic displacement of SMH, and 24 hours prone posturing. Displacement of SMH was assessed by digital photography, and choroidal neovascularization (CNV) was reclassified using angiography. PDT was applied when indicated within 1 to 12 days postoperatively. Adequate displacement of SMH allowed visualization of CNV within 24 hours in three of five patients. One patient with large SMH of 7 weeks duration had partial displacement of SMH. Three patients were reclassified with classic CNV after tPA-SF6 injection, and successfully underwent PDT. Intravitreal tPA and SF6 assisted pneumatic displacement of SMH is a safe and effective intervention. This technique facilitates more accurate angiographic classification of CNV. PDT may be sequentially and rapidly applied as early as 1 day after injections. The technique may be offered to patients with neovascular MD presenting with acute SMH.

Extensive submacular haemorrhage in polypoidal choroidal vasculopathy managed by sequential gas displacement and photodynamic therapy: a pilot study of one‐year follow up

Polypoidal choroidal vasculopathy (PCV) with peculiar vascular lesions presents frequently as recurrent submacular haemorrhage. The best treatment is still not certain. It is the authors' objective to evaluate the 1-year safety and efficacy of photodynamic therapy (PDT) using verteporfin for persistent macular PCV after pneumatic displacement of the massive submacular haemorrhage with intravitreal perfluoropropane (C(3)F(8)). A prospective, non-comparative, interventional case series on patients with extensive and thick submacular haemorrhage secondary to PCV, which was displaced pneumatically with intravitreal pure 0.4 ml C(3)F(8). Fluorescein angiography and indocyanine green angiography were repeated 1-2 weeks later to delineate any persistent active leaking polypoidal lesions, which were then treated with PDT. Retreatment might be considered in each follow up at every 3 months. Six eyes of six patients with the mean age of 53.6 years had been recruited and completed 1-year follow up. The mean baseline Snellen equivalent best-corrected visual acuity (BCVA) was 6/92 and the mean final BCVA at 1 year was 6/17. The mean improvement in logMAR BCVA after the sequential treatments was seven lines (range +3 to +19 lines) (Wilcoxon signed-ranks test, P = 0.03). All patients had at least moderate visual gains. No patient suffered serious complications from PDT. This first report on combined treatment with intravitreal gas injection and sequential PDT on PCV seems to be a well-tolerated option. Further comparative studies with larger sample size and longer follow up are warranted.

Bilateral Sequential Photodynamic Therapy for Sub-retinal Neovascularization With Type 2A Parafoveal Telangiectasis

To report the results of repeated bilateral sequential photodynamic therapy (PDT) with verteporfin for sub-retinal neovascularization associated with parafoveal telengiectasia. Interventional case series. Three patients (minimum of 6-month follow-up) were analyzed after bilateral sequential PDT for parafoveal telengiectasia-associated sub-retinal neovascularization. Mean age was 53.3 +/- 2.1 years. Mean and median follow-up duration were 12.3 and 10 months, respectively. Mean initial Early Treatment of Diabetic Retinopathy Study chart letter acuity was 30.6 in right eyes and 19 in left eyes, and at month 6, it was 30.6 in right eyes and 22.3 in left eyes. All patients received bilateral treatment three times; one eye received a fourth treatment. The greatest linear diameter was between 2310 and 5400 microm. PDT is a viable treatment for sub-retinal neovascularization associated with parafoveal telengiectasia. Bilateral sequential treatment is a convenient way to treat bilateral disease.

Alterations in Mitochondrial and Apoptosis-regulating Gene Expression in Photodynamic Therapy-resistant Variants of HT29 Colon Carcinoma Cells¶

Abstract Photodynamic therapy (PDT) is a novel cancer therapy inducing irreversible photodamage to tumor tissue via photosensitizer-mediated oxidative cytotoxicity. The cellular and molecular responses associated with PDT are only partially understood. We have reported previously the generation of several photosensitizer-specific PDT-resistant cell variants of HT29 human colon adenocarcinoma cells by selecting cells from sequential PDT treatment using different photosensitizers. In this report, we describe the use of messenger RNA (mRNA) differential display to identify genes that were differentially expressed in the parental HT29 cells compared with their resistant variants. In comparison with parental HT29 cells, mRNA expression was increased in the PDT-resistant cell variants for BNIP3, estrogen receptor–binding fragment–associated gene 9, Myh-1c, cytoplasmic dynein light chain 1, small membrane protein I and differential dependent protein. In contrast, expression in the PDT-resistant variants was down...

Alterations in mitochondrial and apoptosis regulating gene expression in photodynamic therapy resistant variants of HT29 colon carcinoma cells

Photodynamic therapy (PDT) is a novel cancer therapy inducing irreversible photodamage to tumor tissue via photosensitizer-mediated oxidative cytotoxicity. The cellular and molecular responses associated with PDT are only partially understood. We have reported previously the generation of several photosensitizer-specific PDT-resistant cell variants of HT29 human colon adenocarcinoma cells by selecting cells from sequential PDT treatment using different photosensitizers. In this report, we describe the use of messenger RNA (mRNA) differential display to identify genes that were differentially expressed in the parental HT29 cells compared with their resistant variants. In comparison with parental HT29 cells, mRNA expression was increased in the PDT-resistant cell variants for BNIP3, estrogen receptor-binding fragment-associated gene 9, Myh-1c, cytoplasmic dynein light chain 1, small membrane protein I and differential dependent protein. In contrast, expression in the PDT-resistant variants was downregulated for NNX3, human HepG2 3' region Mbol complementary DNA, glutamate dehydrogenase, hepatoma-derived growth factor and the mitochondrial genes coding for 16S ribosomal RNA (rRNA) and nicotinamide adenine dinucleotide (NADH) dehydrogenase subunit 4. The reduction for mitochondrial 16S rRNA in the PDT-resistant variants was confirmed by Northern blotting, and the elevated expression of the proapoptotic BNIP3 in the PDT-resistant variants was confirmed by Northern and Western blotting analysis. We also examined the expression of some additional apoptosis-regulating genes using Western blotting. We show an increased expression of Bcl-2 and heat shock protein 27 and a downregulation of Bax in the PDT-resistant variants. In addition, the mutant p53 levels in the parental HT29 cells were reduced substantially in the PDT-resistant variants. We suggest that the altered expression in several mitochondrial and apoptosis-regulating genes contributes to PDT resistance.