PET Imaging of Acidic Tumor Environment With 89Zr-labeled pHLIP Probes

Bauer, David; Visca, Hannah; Weerakkody, Anuradha; Carter, Lukas M.; Samuels, Zachary V.; Kaminsky, Spencer; Andreev, Oleg A.; Reshetnyak, Yana K.; Lewis, Jason S.

doi:10.3389/fonc.2022.882541

Cited by 14 publications

(16 citation statements)

References 58 publications

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“…The half-life of fluorescent pHLIP(Laa)-STINGa in a mouse was established to be about 6 times higher compared to STINGa alone, a significantly improved PK. Slow blood clearance of other pHLIP imaging and therapeutic agents in animals has previously been observed ( 12 , 39 , 40 ) and confirmed in humans. Tumor targeting was confirmed by imaging.…”

Section: Discussionsupporting

confidence: 56%

“…A 4T1 tumor contains a smaller population of all immune cells (31% of all tumor cells) and a high population of CD11b + myeloid cells (75% of CD45 + cells). Also, like CT26 tumors, 4T1 tumors are acidic and very well targeted by pHLIP ( 12 , 14 , 39 ). However, a CT26 tumor has 3,023 single nucleotide variations (SNVs) and 362 short indels, while 4T1 tumors have a lower mutational burden, with 505 SNVs and 20 short indel ( 49 ).…”

Section: Discussionmentioning

confidence: 99%

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Eradication of tumors and development of anti-cancer immunity using STINGa targeted by pHLIP

et al. 2022

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Despite significant progress in the development of novel STING agonists (STINGa), applications appear to be challenged by the low efficiency and poor selectivity of these agents. A pH Low Insertion Peptide (pHLIP) extends the lifetime of a STINGa in the blood and targets it to acidic cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), myeloid derived suppressor cells (mMDSCs) and dendritic cells (DCs). CAFs constitute 25% of all live cells within CT26 tumors, and M2-type TAMs and mMDSCs are the most abundant among the immune cells. The resulting activation of cytokines within the tumor microenvironment (TME) triggers the eradication of small (100 mm3) and large (400-700 mm3) CT26 tumors in mice after a single dose of pHLIP-STINGa. The tumor stroma was destroyed (the number of CAFs was reduced by 98%), intratumoral hemorrhage developed, and the level of acidity within the TME was reduced. Further, no tumors developed in 20 out of 25 tumor-free mice re-challenged by an additional injection of cancer cells. The therapeutic effect on CT26 tumors was insignificant in nude mice, lacking T-cells. Thus, targeted delivery of STINGa to tumor stroma and TAMs induces activation of signaling, potentially resulting in the recruitment and infiltration of T-cells, which gain access to the tumor core. The cytotoxic activity of T-cells is not impaired by an acidic environment and immune memory is developed.

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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Eradication of tumors and development of anti-cancer immunity using STINGa targeted by pHLIP

et al. 2022

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“…Novel imaging probes have been developed to assess the acidic TME. 89 Zr-labeled pH-low insertion peptide is a radiopharmaceutical imaging probe for in vivo analysis to quantify the acidic TME using positron emission tomography, and has potential clinical applications ( 62 ). Acido-chemical exchange saturation transfer magnetic resonance imaging can measure the extracellular pH of the TME using the ratio of two pH-dependent signals, and may be useful in revealing the association between urine pH and pH of the TME ( 63 , 64 ).…”

Section: Future Directions Of Alkalization Therapymentioning

confidence: 99%

Clinical review of alkalization therapy in cancer treatment

et al. 2022

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One of the most unique characteristics of cancer metabolism is activated aerobic glycolysis, which is called the “Warburg effect”, and is a hallmark of cancer. An acidic tumor microenvironment (TME) resulting from activated anaerobic glycolysis is associated with cancer progression, multi-drug resistance, and immune escape. Several in vitro and in vivo studies reported that neutralization of the acidic TME by alkalizing agents, such as bicarbonate, resulted in the suppression of cancer progression and a potential benefit for anti-cancer drug responses. In clinical settings, alkalizing effects were achieved not only by alkalizing agents, but also by a following a particular diet. An epidemiological study demonstrated that more fruits and vegetables and less meat and dairy products are associated with an increase in urine pH, which may reflect the alkalizing effect on the body. However, it remains unclear whether alkaline dietary intervention improves the effects of cancer treatment. Moreover, there are few clinical reports to date regarding cancer treatments being performed on patients together with alkalization therapy. In this review, we investigated whether alkalization therapy, which includes an alkaline diet and/or alkalizing agents, improves cancer treatment.

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“…( 47 ) Additionally, pHLIP can be conjugated to other optical dyes e.g., QC1 for optoacoustic imaging and can be radiolabeled for PET imaging. ( 51, 52 ) In this work, we combine the sensitivity of SWIR imaging to ICG with the tumor selectivity of pHLIP for preclinical tumor resection in an orthotopic murine breast model. We show that a commercially available SWIR imaging system has significantly improved sensitivity over widely used commercial imaging system IVIS ® for ICG imaging.…”

Section: Introductionmentioning

confidence: 99%

Preclinical shortwave infrared tumor screening and resection via pHLIP ICG under ambient lighting conditions

Larney

Kim

Roberts

et al. 2022

Preprint

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There is a critical need to improve optical imaging that will lead to its widespread acceptance for routine clinical procedures. Shortwave infrared (SWIR, 900 to 1700nm) imaging has demonstrated clear advantages over visible and near infrared imaging (reduced autofluorescence with improved contrast, resolution, and sensitivity at tissue depth). Here we show that the previously reported compound, pH low insertion peptide (pHLIP) conjugated to indocyanine green (ICG, pHLIP ICG) currently in clinical trials, serves as an excellent candidate for SWIR imaging protocols. SWIRs increased sensitivity enabled preclinical tumor screening and resection at exposure times as low as 0.1 ms with acceptable signal to noise and contrast to noise ratios. Imaging was performed under ambient lighting conditions, and SWIRs sensitivity enabled an extended surgical resection window up to 96 hrs post injection in an orthotopic breast cancer mouse model. This work provides a direct precedent for the clinical translation of SWIR pHLIP ICG imaging for cancer resection.

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PET Imaging of Acidic Tumor Environment With 89Zr-labeled pHLIP Probes

Cited by 14 publications

References 58 publications

Eradication of tumors and development of anti-cancer immunity using STINGa targeted by pHLIP

Eradication of tumors and development of anti-cancer immunity using STINGa targeted by pHLIP

Clinical review of alkalization therapy in cancer treatment

Preclinical shortwave infrared tumor screening and resection via pHLIP ICG under ambient lighting conditions

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