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We have previously shown that a radioactive (123I)-analog of methyl 3-(1′-(iodobexyloxy) ethyl-3-devinylpyropheophorbide-a (PET-ONCO), derived from chlorophyll-a can be used for positron emission tomography (PET) imaging of a variety of tumors, including those where 18F-FDG shows limitations. In this study, the photodynamic therapy (PDT) efficacy of the corresponding non-radioactive photosensitizer (PS) was investigated in a variety of tumor types (NSCLC, SCC, adenocarcinoma) derived from lung cancer patients in mice tumor models. The in vitro and in vivo efficacy was also investigated in combination with doxorubicin, and a significantly enhanced long-term tumor response was observed. The toxicity and toxicokinetic profile of the iodinated PS was also evaluated in male and female Sprague-Dawley rats and Beagle dog at variable doses (single intravenous injections) to assess reversibility or latency of any effects over a 28-day dose free period. The no-observed-adverse-effect (NOAEL) of the PS was considered to be 6.5 mg/kg for male and female rats, and for dogs, 3.45 mg/kg, the highest dose levels evaluated, respectively. The corresponding plasma Cmax and AYClast for male and female rats were 214,000 and 229,000 ng/mL and 3,680,000 and 3,810,000 h * ng/mL, respectively. For male and female dogs, the corresponding plasma Cmax and AYClast were 76,000 and 92,400 ng/mL and 976,000 and 1,200,000 h * ng/mL, respectively. [ABSTRACT FROM AUTHOR]

To determine the impact of delivery vehicles in photosensitizing efficacy of HPPH, a hydrophobic photosensitizer was dissolved in various formulations: 1% Tween 80/5% dextrose, Pluronic P‐123 and Pluronic F‐127 in 0.5%, 1% and 2% phosphate buffer solutions (PBS). HPPH was also conjugated to Pluronic F‐127, and the resulting conjugate (PL‐20) was formulated in PBS. Among the different delivery vehicles, only Pluronic P‐123 displayed significant vehicle cytotoxicity, whereas Pluronic F127 was nontoxic. Compared to PL‐20, HPPH formulated in Tween80 and Pluronic F‐127 showed higher cell‐uptake, but lower long‐term retention in Colon26 cell compared to PL‐20. The higher retention of PL‐20 was similarly observed during in vivo uptake with BALB/c mice baring Ct26 tumors. In contrast to the in vitro uptake experiments, PL‐20 showed slightly higher uptake compared to HPPH formulated in Tween or Pluronic‐F127. A significant difference in pharmacokinetic profile was also observed between the HPPH‐Pluronic formulation and PL‐20. Under similar in vivo treatment parameters (drug dose 0.47 µmol kg−1, light dose: 135 J cm−2 at 24 h post‐injection of PS), HPPH formulated either in Tween or Pluronic F‐127 formulation showed similar in vivo PDT efficacy (20–30% tumor cure on day 60), whereas PL‐20 showed 40% tumor cure (day 60). [ABSTRACT FROM AUTHOR]

We report herein a simple and efficient approach to the synthesis of a variety of meso-substituted purpurinimides. The reaction of meso -substituted purpurinimide with N-bromosuccinimide regioselectively introduced a bromo functionality at the 20-position, which on further reaction with a variety of boronic acids under Suzuki reaction conditions yielded the corresponding meso-substituted analogues. Interestingly, the free base and the metalated analogues showed remarkable differences in photosensitizing efficacy (PDT) and tumor-imaging ability. For example, the free-base conjugate showed significant in vitro PDT efficacy, but limited tumor avidity in mice bearing tumors, whereas the corresponding NiII derivative did not produce any cell kill, but showed excellent tumor-imaging ability at a dose of 0.3 μmol kg−1 at 24, 48, and 72 h post-injection. The limited PDT efficacy of the NiII analogue could be due to its inability to produce singlet oxygen, a key cytotoxic agent required for cell kill in PDT. Based on electrochemical and spectroelectrochemical data in DMSO, the first one-electron oxidation (0.52 V vs. SCE) and the first one-electron reduction (−0.57-0.67 V vs. SCE) of both the free base and the corresponding NiII conjugates are centered on the cyanine dye, whereas the second one-electron reduction (−0.81 V vs. SCE) of the two conjugates is assigned to the purpurinimide part of the molecule. Reduction of the cyanine dye unit is facile and occurs prior to reduction of the purpurinimide group, which suggests that the cyanine dye unit as an oxidant could be the driving force for quenching of the excited triplet state of the molecules. An interaction between the cyanine dye and the purpurinimide group is clearly observed in the free-base conjugate, which compares with a negligible interaction between the two functional groups in the NiII conjugate. As a result, the larger HOMO-LUMO gap of the free-base conjugate and the corresponding smaller quenching constant is a reason to decrease the intramolecular quenching process and increase the production of singlet oxygen to some degree. [ABSTRACT FROM AUTHOR]

This report presents the synthesis and folate receptor target-specificity of amino-functionalized polyacrylamide nanoparticles (AFPAA NPs) for near-infrared (NIR) fluorescence imaging of cancer. For the synthesis of desired nano-constructs, the AFPAA NPs (hereafter referred to as NPs) were reacted with a NIR cyanine dye (CD) bearing carboxylic acid functionality by following our previously reported approach, and the resulting conjugate (NP-CD) on further reaction with folic acid (FA) resulted in a new nano-construct, FA-NP-CD, which demonstrated significantly higher uptake in folate receptor-positive breast cancer cells (KB+) and in folate receptor over-expressed tumors in vivo. The target-specificity of these nanoparticles was further confirmed by inhibition assay in folate receptor-positive (KB+) and -negative (HT-1080) cell lines. To show the advantages of polyacrylamide (PAA)-based NPs in folate receptor target-specificity, the CD used in preparing the FA-NP-CD construct was also reacted with folic acid alone and the synthetic conjugate (CD-FA) was also investigated for its target-specificity. Interestingly, in contrast to NPs (FA-NP-CD), the CD-FA conjugate did not show any significant in vitro or in vivo specificity toward folate receptors, showing the advantages of PAA-based nanotechnology in delivering the desired agent to tumor cells. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]