Liyang Cui

Targeting-Triggered Porphysome Nanostructure Disruption for Activatable Photodynamic Therapy

Photodynamic therapy (PDT) and photothermal therapy (PTT) possess advantages over the conventional therapies with additional treatment selectivity achieved with local laser irradiation. Comparing to PTT that ablates target tissue via thermal necrosis, PDT induces target cell death via singlet oxygen without damaging the underling connective tissue, thus preserving its biological function. Activatable photosensitizers provide an additional level of treatment selectivity via the disease-associated activation mechanism. In this study, folate-conjugated porphysomes are introduced as targeting-triggered activatable nano-sized beacons for PDT. Porphysomes are reported previously as the most stable and efficient delivery system of porphyrin, but their nanostructure converts the singlet oxygen generation mechanism to thermal ablation mechanism. By folate-receptor-mediated endocytosis, folate-porphysomes are internalized into cells rapidly and resulted in efficient disruption of nanostructures, thus switching back on the photodynamic activity of the densely packed porphyrins for effective PDT. In both in vitro and in vivo studies, folate-porphysomes can achieve folate receptor-selective PDT efficacy, which proves the robustness of targeting-triggered PDT activation of porphysome nanostructure for highly selective tumor ablation. The formulation of porphysomes can be modified with other targeting ligands as activatable photosensitizers for personalized treatment in future.

Multimodal Image-Guided Surgical and Photodynamic Interventions in Head and Neck Cancer: From Primary Tumor to Metastatic Drainage

Purpose: The low survival rate of head and neck cancer (HNC) patients is attributable to late disease diagnosis and high recurrence rate. Current HNC staging has inadequate accuracy and low sensitivity for effective diagnosis and treatment management. The multimodal porphyrin lipoprotein-mimicking nanoparticle (PLP), intrinsically capable of positron emission tomography (PET), fluorescence imaging, and photodynamic therapy (PDT), shows great potential to enhance the accuracy of HNC staging and potentially HNC management. Experimental Design: Using a clinically relevant VX-2 buccal carcinoma rabbit model that is able to consistently develop metastasis to regional lymph nodes after tumor induction, we investigated the abilities of PLP for HNC diagnosis and management. Results: PLPs facilitated accurate detection of primary tumor and metastatic nodes (their PET image signal to surrounding muscle ratios were 10.0 and 7.3, respectively), and provided visualization of the lymphatic drainage from tumor to regional lymph nodes by both preoperative PET and intraoperative fluorescence imaging, allowing the identification of unknown primaries and recurrent tumors. PLP-PDT significantly enhanced cell apoptosis in mouse tumors (73.2% of PLP-PDT group vs 7.1% of PLP alone group) and demonstrated complete eradication of primary tumors and obstruction of tumor metastasis in HNC rabbit model without toxicity in normal tissues or damage to adjacent critical structures. Conclusions: PLPs provide a multimodal imaging and therapy platform that could enhance HNC diagnosis by integrating PET/computed tomography and fluorescence imaging, and improve HNC therapeutic efficacy and specificity by tailoring treatment via fluorescence-guided surgery and PDT. Clin Cancer Res; 22(4); 961–70. ©2015 AACR.

Organized Aggregation of Porphyrins in Lipid Bilayers for Third Harmonic Generation Microscopy.

Nonlinear optical microscopy has become a powerful tool for high-resolution imaging of cellular and subcellular composition, morphology, and interactions because of its high spatial resolution, deep penetration, and low photo-damage to tissue. Developing specific harmonic probes is essential for exploiting nonlinear microscopic imaging for biomedical applications. We report an organized aggregate of porphyrins (OAP) that formed within lipidic nanoparticles showing fingerprint spectroscopic properties, structure-associated second harmonic generation, and superradiant third harmonic generation. The OAP facilitated harmonic microscopic imaging of living cells with significantly enhanced contrast. The structure-dependent switch between harmonic (OAP-intact) and fluorescence (OAP-disrupted) generation enabled real-time multi-modality imaging of the cellular fate of nanoparticles. Robustly produced under various conditions and easily incorporated into pre-formed lipid nanovesicles, OAP provides a biocompatible nanoplatform for harmonic imaging.

Molecular Imaging Reveals Trastuzumab-Induced Epidermal Growth Factor Receptor Downregulation In Vivo

Previous in vitro studies demonstrated that treating tumors expressing both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 with trastuzumab resulted in increased EGFR homodimerization and subsequent rapid downregulation of EGFR. We investigated whether molecular imaging using near-infrared fluorescence (NIRF) imaging and PET probes could sensitively detect trastuzumab-induced EGFR downregulation in vivo. Methods: The F(ab′)2 antibody fragment PaniF(ab′)2 was generated by digesting the anti-EGFR monoclonal antibody panitumumab. PaniF(ab′)2 was labeled with either a NIRF dye or 68Ga, and optical imaging and small-animal PET imaging of Dye-PaniF(ab′)2 and 68Ga-PaniF(ab′)2, respectively, were performed in HT-29 tumor–bearing nude mice treated with trastuzumab or untreated control. Results: Longitudinal NIRF imaging studies revealed significantly reduced tumor uptake of Dye-PaniF(ab′)2 on days 5 and 7 in trastuzumab-treated HT-29 tumors, compared with control. Western blotting confirmed the downregulation of EGFR after treatment with trastuzumab. Small-animal PET on day 5 after trastuzumab treatment also demonstrated decreased 68Ga-PaniF(ab′)2 uptake in trastuzumab-treated HT-29 tumors. The tumor uptake value of 68Ga-PaniF(ab′)2 obtained from PET imaging had an excellent linear correlation with the uptake value measured using biodistribution. Conclusion: The downregulation of EGFR induced by trastuzumab treatment could be detected noninvasively using optical and PET imaging. This molecular imaging strategy could provide a dynamic readout of changes in the tumor signaling and may facilitate the noninvasive monitoring of the early tumor response to drug treatment.

Multimodal Nanoparticle for Primary Tumor Delineation and Lymphatic Metastasis Mapping in a Head-and-Neck Cancer Rabbit Model

64 Cu-porphysome nanoparticles enable superior delineation of neoplastic tissues, metastatic lymph nodes, and vascular drainage on head and neck cancer orthotopic rabbit model using positron emission tomography imaging. Additionally, the nanoparticles exhibit selective fluorescence activation in tumor and metastatic lymph nodes, which permits intraoperative real-time visualization of disease tissues to precisely define surgical margins and prevents collateral damage during surgeries.

Evaluation of 188Re-MAG2-RGD-bombesin for potential prostate cancer therapy.

Glu-RGD-bombesin (RGD-BBN) is a heterodimeric peptide that contains motifs recognizing both integrin α(v)β(3) and gastrin releasing peptide receptor (GRPR). We evaluated here (188)Re (t(1/2)=16.9 h) labeled RGD-BBN as a potential agent for radionuclide therapy of prostate cancer. RGD-BBN was conjugated with S-benzoylmercaptoacetylglycylglycyl (MAG(2)), and then labeled with (99m)Tc or (188)Re, respectively. The dual-receptor binding affinity of MAG(2)-RGD-BBN was investigated by a radioligand competition binding assay. Biodistribution study of (188)Re-MAG(2)-RGD-BBN was carried out in normal BALB/c mice and PC-3 human prostate tumor-bearing nude mice. Gamma imaging studies were performed in PC-3 tumor-bearing nude mice. Biodistribution in normal mice showed that both (99m)Tc and (188)Re-labeled MAG(2)-RGD-BBN possessed high pancreas uptake due to the high GRPR expression of this organ. Gamma imaging with both (99m)Tc and (188)Re-labeled RGD-BBN in PC-3 tumor-bearing nude mice demonstrated high tumor uptake. The PC-3 tumors were clearly visible at 1 postinjection, with high contrast to the contralateral background. The use of chelator MAG(2) enables successful and high-yield (99m)Tc and (188)Re radiolabeling of RGD-BBN with favorable tumor targeting specificity. Further optimization may allow potential clinical application of (188)Re-MAG(2)-RGD-BBN for tumor-targeted radionuclide therapy.

Nanoparticle-Enabled Selective Destruction of Prostate Tumor Using MRI-Guided Focal Photothermal Therapy.

The Magnetic Resonance Imaging (MRI)‐guided focal laser therapy has shown early promise in Phase 1 trial treating low/intermediate‐risk localized prostate cancer (PCa), but the lack of tumor selectivity and low efficiency of heat generation remain as drawbacks of agent‐free laser therapy. Intrinsic multifunctional porphyrin‐nanoparticles (porphysomes) have been exploited to treat localized PCa by MRI‐guided focal photothermal therapy (PTT) with significantly improved efficiency and tumor selectivity over prior methods of PTT, providing an effective and safe alternative to active surveillance or radical therapy.

PET Tracers Based on 86Y

Positron emission tomography (PET) has become a powerful tool for probing biochemical processes in living subjects. PET imaging depends largely on the development of novel PET tracers labeled with positron-emitting radionuclides. Since the four traditional PET isotopes (18F, 11C, 13N, and 15O) are produced in a cyclotron and are short-lived, their use for long-term observation of biological processes in vivo is limited. In the last decades, extensive research in the development of other unconventional radionuclides (such as 64Cu, 68Ga, 89Zr, 86Y, and 124I) labeled tracers with half-lives complementary to the biological properties of their targeting agents has been conducted. Among these tracers, 86Y-based PET tracers have gained increasing attention since they are ideal surrogates for in vivo determination of biodistribution and dosimetry of therapeutic 90Y (pure β - emitter) pharmaceuticals. In this review article, we will brief introduce the physical characteristics, production, and radiochemistry of 86Y, and will summarize the current 86Y-based PET tracers used for molecular imaging and cancer detection in animal studies and in clinical trials.

Porphyrin-lipid assembled HDL-like nanovesicles for fluorescence imaging and PDT treatment of orthotopic brain glioma tumor

Glioblastoma is the most lethal form of brain tumors and one of the most fatal human cancers with universal recurrence post-surgical procedures and common failure in the salvage therapies. Fluorescence agents introduced to facilitate the identification of cancerous tissues in surgical resection are facing challenges such as low sensitivity and specificity and ineffective delivery to intracerebral tumor via systemic administration. Recently, we have developed a porphyrin-lipid assembled HDL-like nanovesicle (porphyHDL) with sub 20 nm in size. The highly packed porphyrin molecules in the assembly allows for the intrinsically labeling with Cu-64 and provides fluorescence emission and great PDT potency upon laser irradiation, thus making this nanocomplex a multifunctional reagent suitable for pre- and intra-operative imaging and surgical bed clean-up.

Technetium 99m–Labeled VQ Peptide: A New Imaging Agent for the Early Detection of Tumors or Premalignancies

There is a critical need to develop diagnostic procedures enabling early detection of tumors while at a curable stage. Technetium 99m (99mTc)-labeled VQ peptide (99mTc-HYNIC-VQ) identified through screening phage display peptide libraries against fresh human colonic adenomas was prepared and evaluated for tumor detection. 99mTc-HYNIC-VQ was prepared by a non-SnCl2 method with more than 99% radiochemical purity. The biodistribution in the HT-29 tumor model showed that although the absolute tumor uptake values were relatively low (0.60 ± 0.09, 0.41 ± 0.09, 0.36 ± 0.18, and 0.19 ± 0.08 %ID/g at 0.5, 1, 2, and 4 hours postinjection, respectively), the tumor uptake was higher than that of any of the other organs except for the kidneys at any time point examined, which led to the high tumor to nontarget ratios. The tumors and inflammation were clearly visualized with high contrast. Although the mechanism of accumulation of radiolabeled VQ peptide in tumors and inflammation needs to be further investigated, 99mTc-HYNIC-VQ is a promising imaging agent for the early detection of tumors or premalignancies, at least for screening patients with a high risk of developing cancers.