1. Molecular specific photoacoustic imaging with targeted nanoparticles.

Assessment of molecular signatures of tumors in addition to their anatomy and morphology is desired for effective diagnostic and therapeutic procedures. Development of in vivo imaging techniques that can identify and monitor molecular composition of tumors remains an important challenge in pre-clinical research and medical practice. My graduate work involved development of a molecular photoacoustic imaging technique that can visualize the presence and activity of one or more important cancer biomarkers utilizing the effect of plasmon resonance coupling between molecular targeted gold nanoparticles. For example, our very highly cited paper published in Nanoletters showed Epidermal Growth Factor Receptor (EGFR) activity using spectral analysis of photoacoustic images revealed profound changes in the optical absorption of systemically delivered EGFR-targeted gold nanospheres due to their molecular interactions with tumor cells overexpressing EGFR. Ultrasound-guided molecular photoacoustic imaging can potentially aid in tumor diagnosis, selection of customized patient-specific treatment, and monitor the therapeutic progression and outcome in vivo.

Selected Publications:

Mallidi, T. Larson, J. Aaron, K. Sokolov, and S. Emelianov, “Molecular specific optoacoustic imaging with plasmonic nanoparticles,” Optics Express, 15, 6583-6588, 2007. PMID: 19546967

Mallidi, T. Larson, J.Tam, K. Sokolov and S. Emelianov, “Multi-wavelength photoacoustic imaging and plasmon resonance coupling of gold nanoparticles for selective detection of cancer”, Nano Letters, 9, 2825-2831, 2009. PMID: 19572747. PMC2898720.

Mallidi, S. Kim, A. Karpiouk, P. Joshi, K. Sokolov and S. Emelianov, “Ultrasound-guided visualization of the molecular functionality of tumor cells using targeted gold nanoparticles,” Photoacoustics, 3: 26-34, 2015. PMID: 25893171. PMC4398809.

  1. Photoacoustic imaging guided therapy

Currently our research focuses on image-guided light based therapies such as photothermal therapy, photodynamic therapy (PDT, a photochemistry based cytotoxic therapy), vascular targeted chemotherapy, and related therapeutic combinations for pancreatic, brain and skin cancers guided using functional information obtained from ultrasound and photoacoustic imaging techniques Primary parameters such as tumor viability and necrotic volumes, vasculature, perfusion, blood oxygen saturation, and glucose metabolism will be measured and the status of these parameters pre-therapy and changes in the parameters post-therapy will be utilized to design (e.g., dose and sequence) and monitor (predict efficacy) therapeutic strategies. Recent work in this topic has been selected as Cover Feature in the Theranostics Journal.

Selected Publications:

A. Claus, A. Sweeney, DM. Sankepalle, B. Li, D. Wong, M. Xavierselvan, S. Mallidi,  “3D Ultrasound-Guided Photoacoustic Imaging to Monitor the Effects of Suboptimal Tyrosine Kinase Inhibitor Therapy in Pancreatic Tumors”. Front Oncol. 2022                

Mallidi, G. P. Luke, S. Emelianov, “Photoacoustic imaging in cancer detection, diagnosis, and treatment guidance”, Trends in Biotechnology, 29 (5), 213-221, 2011. PMID: 21324541. PMC3080445.

Mallidi, K. Watanabe, D. Timerman, and T. Hasan, “Prediction of tumor recurrence and therapy monitoring using ultrasound-guided photoacoustic imaging,” Theranostics, 5(3): 289-301, 2014. PMID: 25553116. PMC4279192. (Selected for Cover Feature)

Mallidi, B. Q. Spring and T. Hasan, “Optical Imaging, Photodynamic Therapy and Optically-triggered Combination treatments,” The Cancer Journal, 21(3): 194-205, 2015. PMID: 26049699. PMC4459538.

Mallidi, S. Anbil, A. L. Bulin, G. Obaid, M. Ichikawa, T. Hasan, “Beyond the Barriers of Light Penetration: Strategies, Perspectives and Possibilities for Photodynamic Therapy,” Theranostics 2016; 6(13): 2458-2487. PMC5118607.

Z. Petrovic, M. Xavierselvan, M. Kuriakose, M. D. Kennedy, C. D. Nguyen, J. J. Batt, K. B. Detels, S. Mallidi, “Mutual impact of clinically translatable near-infrared dyes on photoacoustic image contrast and in vitrophotodynamic therapy efficacy,” J. Biomed. Opt. 25(6) 063808. PMID 32112541

  1. Clinical translation of patient-specific, image-guided Photodynamic therapy dosimetry for cancer:

Photodynamic therapy (PDT), a photochemistry-based therapeutic modality, is being used clinically for several applications such as the Age-macular degeneration and actinic keratosis. For the treatment modality to gain further traction in dermatologic and oncologic applications in clinic, there is high need for patient-specific photodynamic therapy (PDT). We performed a first clinical study comparing the ability of discrete PS fluorescence-based metrics (absolute and percent PS photobleaching and PS reaccumulation post-PDT) to predict the clinical phototoxic response resulting from 5-aminolevulinic acid PDT. We also compared the metrics with discrete SOL (DSOL)-based metrics (DSOL counts pre-PDT and change in DSOL counts pre/post-PDT).  Furthermore, we recently demonstrated efficacy of battery powered light sources and smart phoen based imaging systems to treat oral cancer patients in low resource settings in India. My expertise in ALA-PDT based clinical trials and evaluation of photosensitizer fluorescence based treatment prediction metrics will be invaluable in the context of the current proposal.

Selected Publications:

Mallidi, S. Anbil, S. Lee, D. Manstein, S. Elrington, G. Kositratna, D. Schoenfeld, B. W. Pogue, S. J. Davis, and T. Hasan “Photosensitizer fluorescence and singlet oxygen luminescence as dosimetric predictors of PDT-induced clinical erythema,” Journal of Biomedical Optics, 19(2):028001, 2014. PMID: 24503639. PMC3915169.

Mallidi, Z. Mai, I. Rizvi, S. Arnason, J. Celli and T. Hasan, “PDT in low resource settings: A proof-of-principle in vivo study in a xenograft model of squamous cell carcinoma using LED illumination”, Journal of Biomedical Optics, 20(4): 048003, 2015. PMID: 25909707. PMC4408448.

Mallidi, A.P. Khan, H. Liu , L. Daly , G. Rudd , P. Leon , S. Khan , B. Hussain , S. Hasan , S. Siddique , K. Akhtar , M. August , M. Troulis , F. Cuckov , J. Celli and T. Hasan, “Platform for ergonomic intraoral photodynamic therapy using low-cost, modular 3D-printed components: Design, comfort and clinical evaluation”, Scientific Reports, 9: 1830, 2019

S.C. Hester, M. Kuriakose, C. D. Nguyen,and S. Mallidi, “Role of Ultrasound and Photoacoustic Imaging in Photodynamic Therapy for Cancer”. Photochem Photobiol, 96(2): 260-279, 2020. PMID: 31919853

  1. PDT based combination therapies

The ability of tumor cells to adapt to therapeutic regimens by activating alternative survival and growth pathways remains a major challenge in cancer therapy. Therefore, the most effective treatments will involve interactive strategies that target multiple non-overlapping pathways while eliciting synergistic outcomes and minimizing systemic toxicities. We demonstrated that the combination of photodynamic therapy (PDT) with chemo-drug irinotecan produces synergistic benefit for treating pancreatic tumors.  Nanoliposomal irinotecan is approved by the FDA for gemcitabine-refractory metastatic pancreatic cancer. However, the full potential of irinotecan treatment is hindered by several cancer cell survival mechanisms, including ATP-binding cassette G2 (ABCG2) transporter-mediated irinotecan efflux from cells. We demonstrated that benzoporphyrin derivative-based PDT, a photochemical cytotoxic modality that activates the apoptotic pathway, reduced ABCG2 expression to increase intracellular irinotecan levels in pancreatic cancer. Moreover, we show that PDT inhibited survivin expression. Although PDT potentiated irinotecan treatment, we also demonstrated that irinotecan reduced the tumoral expression of monocarboxylate transporter 4, which was upregulated by PDT. Notably, using orthotopic xenograft models, we demonstrate that combination of single low-dose PDT and a subclinical dose of nanoliposomal irinotecan synergistically inhibited tumor growth by 70% for 3 weeks compared with 25% reduction after either monotherapies. Our findings offer new opportunities for the clinical translation of PDT and irinotecan combination therapy for effective pancreatic cancer treatment.

Selected Publications:

H-C Huang*, Mallidi*, C-T. Chiang, Z. Mai and T. Hasan,“Photodynamic therapy synergizes with irinotecan to overcome compensatory mechanisms and improve treatment outcomes in pancreatic cancer”, Cancer Research, 76(5): 1066-77, 2016. PMC4775276. *Equal Authorship

Pigula, H. Huang#, S.Mallidi #, S. Anbil, J. Liu, Z. Mai and T. Hasan, “Size‐dependent Tumor Response to Photodynamic Therapy and Irinotecan Monotherapies Revealed by Longitudinal Ultrasound Monitoring in an Orthotopic Pancreatic Cancer Model”, Photochem Photobiol, 95: 378-386, 2018. #Equal Authorship

Anbil, M. Pigula , H-C. Huang , S. Mallidi , M. Broekgaarden , Y. Baglo , D. M. Simeone , M. Mino-Kenudson , E. V. Maytin , I.Rizvi and T. Hasan “VDR activation and photodynamic priming enable durable low-dose chemotherapy for improved tolerability without compromising efficacy, Molecular Cancer Therapeutics, 2020 (Eprint ahead of publication)

  1. Ultrasound based multi-modal imaging systems:

The effectiveness of an imaging technique is often based on the ability to image quantitatively both morphological and physiological functions of the tissue. I custom-built several imaging modalities based on ultrasound imaging, namely strain imaging and magnetomotive imaging. Biomedical and clinical applications of the developed imaging approaches ranged from microscopic to macroscopic imaging of cardiovascular diseases, cancer detection, diagnosis, therapy, and therapy monitoring.

Selected Publications:

Karpiouk, S.R. Aglyamov, S. Mallidi, J. Shah, W. G. Scott, J. Rubin, and S.Emelianov, “Combined ultrasound and photoacoustic imaging to detect and stage deep vein thrombosis: phantom and ex vivo studies,” Journal of Biomedical Optics, 13(5): 054061, 2008.

Mehrmohammadi, J. Oh, S. Mallidi and S. Emelianov, “Pulsed magneto-motive ultrasound imaging using ultra-small magnetic nanoprobes”, Molecular Imaging, 10(2):102-10. 2011. PMID: 21439255

Qu, S. Mallidi, M. Mehrmohammadi, R. Truby, K. Homan, P. Joshi, Y. Chen, K. Sokolov, and S. Emelianov, “Magneto-photo-acoustic imaging,” Biomedical Optics Express, 2(2), 385-396, 2011. PMID: 21339883

J. Yoon, S. Mallidi, J. M. Tam, J. O. Tam, A. Murthy, K. P. Johnston, K. V. Sokolov, and S. Emelianov, “Utility of biodegradable plasmonic nanoclusters in photoacoustic imaging,” Optics Letters, 35, 3751-3753, 2010.    PMID: 21081985