Hypoxia-Activated Albumin-Binding Exatecan Prodrug for Cancer Therapy.
Ontology highlight
ABSTRACT:
SUBMITTER: Cheng Z
PROVIDER: S-EPMC8757358 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Hypoxia is an important feature of most solid tumors, conferring resistance to radiation and many forms of chemotherapy. However, it is possible to exploit the presence of tumor hypoxia with hypoxia-activated prodrugs (HAPs), agents that in low oxygen conditions undergo bioreduction to yield cytotoxic metabolites. Although many such agents have been developed, we will focus here on TH-302. TH-302 has been extensively studied, and we discuss its mechanism of action, as well as its efficacy in preclinical and clinical studies, with the aim of identifying future research directions.
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Project description:Pancreatic ductal adenocarcinoma (PDAC) presents as an unmet clinical challenge for drug delivery due to its unique hypoxic biology. Vinblastine-N-Oxide (CPD100) is a hypoxia-activated prodrug (HAP) that selectively converts to its parent compound, vinblastine, a potent cytotoxic agent, under oxygen gradient. The study evaluates the efficacy of microfluidics formulated liposomal CPD100 (CPD100Li) in PDAC. CPD100Li were formulated with a size of 95 nm and a polydispersity index of 0.2. CPD100Li was stable for a period of 18 months when freeze-dried at a concentration of 3.55 mg/mL. CPD100 and CPD100Li confirmed selective activation at low oxygen levels in pancreatic cancer cell lines. Moreover, in 3D spheroids, CPD100Li displayed higher penetration and disruption compared to CPD100. In patient-derived 3D organoids, CPD100Li exhibited higher cell inhibition in the organoids that displayed higher expression of hypoxia-inducible factor 1 alpha (HIF1A) compared to CPD100. In the orthotopic model, the combination of CPD100Li with gemcitabine (GEM) (standard of care for PDAC) showed higher efficacy than CPD100Li alone for a period of 90 days. In summary, the evaluation of CPD100Li in multiple cellular models provides a strong foundation for its clinical application in PDAC.
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Project description: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.
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Project description:Due to its abundant chondrogenic matrix and hypoxic tissue, chondrosarcoma is chemo- and radio-resistant. Our group has developed a proteoglycan targeting strategy by using a quaternary ammonium (QA) function as a carrier of DNA alkylating agents to chondrosarcoma environment. Here, we assessed the relevance of this strategy applied to hypoxia-activated prodrugs, by conjugating a QA to 2-nitroimidazole phosphoramidate. This derivative, named as 8-QA, was evaluated respectively to its non-QA equivalent and to a QA-conjugated but non-hypoxia activated. Firstly binding to aggrecan was confirmed from dissociation constant determined by Surface Plasmon Resonance. In vitro, in HEMC-SS chondrosarcoma cells cultured in monolayer and in spheroids, 8-QA showed higher cytotoxic activity in hypoxia versus normoxia, and led to a strong accumulation of cells in S phase and apoptosis. In vivo, a HEMC-SS xenograft model was implanted on SCID mice and characterized for hypoxia by photoacoustic imaging as well as proteoglycan content. When HEMC-SS bearing mice were given 8-QA at 47 ?mol/kg according to a q4d x 6 schedule, a significant 62.1% inhibition of tumor growth was observed, without associated hematological side effects. Mechanistic studies of treated tumors highlighted decrease in mitotic index associated to increase in both p21 and p53S15 markers. Interestingly, 8-QA treatment induced an increase of DNA damages as measured by ?H2AX predominantly found in pimonidazole-positive hypoxic areas. These preclinical results are the first to demonstrate the interest of addressing hypoxia-activated prodrugs selectively to proteoglycan of chondrogenic tumor tissue, as a promising therapeutic strategy.
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Project description:Folate receptor (FR) has proven to be a valuable target for chemotherapy using folic acid (FA) conjugates. However, FA-conjugated chemotherapeutics still have low therapeutic efficacy accompanied with side effects, resulting from complications such as short circulation half-life, limited tumor delivery, as well as high kidney accumulation. Herein, we present a novel FA-conjugated paclitaxel (PTX) prodrug which was additionally conjugated with an Evans blue (EB) derivative for albumin binding. The resulting bifunctional prodrug prolonged blood circulation, enhanced tumor accumulation, and consequently improved tumor therapeutic efficacy. Methods: Fmoc-Cys(Trt)-OH was coupled onto PTX at the 7'-OH position for further synthesis of ester prodrug FA-PTX-EB. The targeting ability was investigated using confocal microscopy and flow cytometry. The pharmacokinetics of this bifunctional compound was also studied. Meanwhile, cell viability was evaluated in normal cells and three cancer cell lines by MTT assay. In vivo therapeutic effect was tested on FR-? overexpressing MDA-MB-231 tumor model. Results: Compared with free PTX, the FA-PTX, PTX-EB and FA-PTX-EB prodrugs increased circulation half-life in mice from 2.19 to 3.82, 4.41, and 7.51 h, respectively. Pharmacokinetics studies showed that the FA-PTX-EB delivered more PTX to tumors than FA-PTX and free PTX. In vitro and in vivo studies demonstrated that FA-EB-conjugated PTX induced potent antitumor activity. Conclusion: FA-PTX-EB showed prolonged blood circulation, enhanced drug accumulation in tumors, higher therapeutic index, and lower side effects than either free PTX or monofunctional FA-PTX and EB-PTX. The results support the potential of using EB for the development of long-acting therapeutics.
| S-EPMC5858514 | biostudies-other
Project description:Cancer chemotherapeutic agents often have a narrow therapeutic index that challenges the maintenance of a safe and effective dose. Consistent plasma concentrations of a drug can be obtained by using a timed-release prodrug strategy. We reasoned that a ribonucleoside 3'-phosphate could serve as a pro-moiety that also increases the hydrophilicity of a cancer chemotherapeutic agent. Herein, we report an efficient route for the synthesis of the prodrug uridine 3'-(4-hydroxytamoxifen phosphate) (UpHT). UpHT demonstrates timed-released activation kinetics with a half-life of approximately 4 h at the approximate plasma concentration of human pancreatic ribonuclease (RNase 1). MCF-7 breast cancer cells treated with UpHT showed decreased proliferation upon co-incubation with RNase 1, consistent with the release of the active drug-4-hydroxytamoxifen. These data demonstrate the utility of a human plasma enzyme as a useful activator of a prodrug.
| S-EPMC3353771 | biostudies-literature
Project description:Angiogenesis is a critical step during tumor progression. Anti-angiogenic therapy has only provided modest benefits in delaying tumor progression despite its early promise in cancer treatment. It has been postulated that anti-angiogenic therapy may promote the emergence of a more aggressive cancer cell phenotype by generating increased tumor hypoxia-a well-recognized promoter of tumor progression. TH-302 is a 2-nitroimidazole triggered hypoxia-activated prodrug (HAP) which has been shown to selectively target the hypoxic tumor compartment and reduce tumor volume. Here, we show that melanoma cells grown under hypoxic conditions exhibit increased resistance to a wide variety of therapeutic agents in vitro and generate larger and more aggressive tumors in vivo than melanoma cells grown under normoxic conditions. However, hypoxic melanoma cells exhibit a pronounced sensitivity to TH-302 which is further enhanced by the addition of sunitinib. Short term sunitinib treatment fails to prolong the survival of melanoma bearing genetically engineered mice (Tyr::CreER; BRafCA;Ptenlox/lox ) but increases tumor hypoxia. Long term TH-302 alone modestly prolongs the overall survival of melanoma bearing mice. Combination therapy of TH-302 with sunitinib further increases the survival of treated mice. These studies provide a translational rationale for combining hypoxic tumor cell targeted therapies with anti-angiogenics for treatment of melanoma.
| S-EPMC5777760 | biostudies-literature
Project description:BackgroundHypoxic niches in solid tumors harbor therapy-resistant cells. Hypoxia-activated prodrugs (HAPs) have been designed to overcome this resistance and, to date, have begun to show clinical efficacy. However, clinical HAPs activity could be improved. In this study, we sought to identify non-pharmacological methods to acutely exacerbate tumor hypoxia to increase TH-302 activity in pancreatic ductal adenocarcinoma (PDAC) tumor models.ResultsThree human PDAC cell lines with varying sensitivity to TH-302 (Hs766t > MiaPaCa-2 > SU.86.86) were used to establish PDAC xenograft models. PDAC cells were metabolically profiled in vitro and in vivo using the Seahorse XF system and hyperpolarized (13)C pyruvate MRI, respectively, in addition to quantitative immunohistochemistry. The effect of exogenous pyruvate on tumor oxygenation was determined using electroparamagnetic resonance (EPR) oxygen imaging. Hs766t and MiaPaCa-2 cells exhibited a glycolytic phenotype in comparison to TH-302 resistant line SU.86.86. Supporting this observation is a higher lactate/pyruvate ratio in Hs766t and MiaPaCa xenografts as observed during hyperpolarized pyruvate MRI studies in vivo. Coincidentally, response to exogenous pyruvate both in vitro (Seahorse oxygen consumption) and in vivo (EPR oxygen imaging) was greatest in Hs766t and MiaPaCa models, possibly due to a higher mitochondrial reserve capacity. Changes in oxygen consumption and in vivo hypoxic status to pyruvate were limited in the SU.86.86 model. Combination therapy of pyruvate plus TH-302 in vivo significantly decreased tumor growth and increased survival in the MiaPaCa model and improved survival in Hs766t tumors.ConclusionsUsing metabolic profiling, functional imaging, and computational modeling, we show improved TH-302 activity by transiently increasing tumor hypoxia metabolically with exogenous pyruvate. Additionally, this work identified a set of biomarkers that may be used clinically to predict which tumors will be most responsive to pyruvate + TH-302 combination therapy. The results of this study support the concept that acute increases in tumor hypoxia can be beneficial for improving the clinical efficacy of HAPs and can positively impact the future treatment of PDAC and other cancers.
| S-EPMC4310189 | biostudies-literature
Project description:Hypoxia is a known feature of aggressive solid tumors as well as a critical hallmark of the niche in aggressive hematologic malignances. Hypoxia is associated with insufficient response to standard therapy, resulting in disease progression and curtailed patients' survival through maintenance of noncycling cancer stem-like cells. A better understanding of the mechanisms and signaling pathways induced by hypoxia is essential to overcoming these effects. Recent findings demonstrate that bone marrow in the setting of hematologic malignancies is highly hypoxic, and that progression of the disease is associated with expansion of hypoxic niches and stabilization of the oncogenic hypoxia-inducible factor-1alpha (HIF1α). Solid tumors have also been shown to harbor hypoxic areas, maintaining survival of cancer cells via the HIF1α pathway. Developing new strategies for targeting hypoxia has become a crucial approach in modern cancer therapy. The number of preclinical and clinical trials targeting low-oxygen tumor compartments or the hypoxic bone marrow niche via hypoxia-activated prodrugs is increasing. This review discusses the development of the hypoxia-activated prodrugs and their applicability in treating both hematologic malignancies and solid tumors. Clin Cancer Res; 23(10); 2382-90. ©2017 AACR.
| S-EPMC5433896 | biostudies-literature