Co-delivery of PARP and PI3K inhibitors by nanoscale metal–organic frameworks for enhanced tumor chemoradiation

Neufeld, Megan J.; DuRoss, Allison N.; Landry, Michel; Winter, Hayden; Goforth, Andrea M.; Sun, Conroy

doi:10.1007/s12274-019-2544-z

Cited by 26 publications

(20 citation statements)

References 57 publications

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“…Therefore, novel anticancer strategies should include immunomodulatory approaches to subvert the tolerance to Nevertheless, a deep understanding of the tumor microenvironment is obligatory to overcome the related obstacles, as the entry and retention of NPs into the tumors, their fate and functionality as well as the challenging clinical translation in humans due to individual differences among patients, and tumors' heterogeneity [46]. Currently, most of the nanostrategies to enhance radiotherapeutic effects relies on the combination with chemotherapeutic agents [47,48], with several clinical trials ongoing [49]; anti-vascular agents [50]; radiosensitizers such as camptothecin [51], DNA repair inhibitors [52] and Pi3K inhibitors [53], which are generally very toxic when delivered systemically in their free forms. Also, the use of inorganic NPs as radiosensitizers has been extensively reported [54,55], despite remaining a challenge for clinical translation.…”

Section: Discussionmentioning

confidence: 99%

Chitosan/γ-PGA nanoparticles-based immunotherapy as adjuvant to radiotherapy in breast cancer

et al. 2020

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Section: Discussionmentioning

confidence: 99%

Chitosan/γ-PGA nanoparticles-based immunotherapy as adjuvant to radiotherapy in breast cancer

et al. 2020

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“…In 2019 Neufeld et al. utilized the Hf‐analogue of UiO‐66 (Hf‐BDC) for co‐delivery of two DNA damage repair inhibitors (DDRis) [34] . Compared to traditional chemotherapeutics, DDRis target the signaling and repair mechanisms of associated with DNA damage.…”

Section: Metal‐framework In Radiation Therapymentioning

confidence: 99%

“…Collectively, these reports establish the potential design of NCP platforms for combined chemotherapy and RT.I n2 019 Neufeld et al utilized the Hf-analogue of UiO-66( Hf-BDC) for co-delivery of two DNA damager epair inhibitors (DDRis). [34] Compared to traditional chemotherapeutics, DDRis target the signaling and repair mechanismso fa ssociated with DNA damage.H ere, the Hf-UiO-66 was synthesized followed by PEGylation and drug loading with talazoparib (T) and buparlisib (B) to obtain (TB@Hf-BDC-PEG) (Figure 7a). In vitro quantification of induced DNA damage via g-H2AX assay revealed that 24 ha fter radiation, most of the DNA damaged isappeared in the control group and Hf-BDC-PEG,i ndicative of efficient DNA repair (Figure 7b).…”

Section: Metal-organic Framework For Chemoradiotherapymentioning

confidence: 99%

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High‐Z Metal–Organic Frameworks for X‐ray Radiation‐Based Cancer Theranostics

Neufeld

Lutzke

Pratx

et al. 2020

Chemistry A European J

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X‐ray radiation is commonly employed in clinical practice for diagnostic and therapeutic applications. Over the past decade, developments in nanotechnology have led to the use of high‐Z elements as the basis for innovative new treatment platforms that enhance the clinical efficacy of X‐ray radiation. Nanoscale metal–frameworks (nMOFs) are coordination networks containing organic ligands that have attracted attention as therapeutic platforms in oncology and other areas of medicine. In cancer therapy, X‐ray activated, high‐Z nMOFs have demonstrated potential as radiosensitizers that increase local radiation dose deposition and generation of reactive oxygen species (ROS). This minireview summarizes current research on high‐Z nMOFs in cancer theranostics and discusses factors that may influence future clinical application.

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“…To broaden their application, phosphoinositide-3-kinase (PI3K) inhibitors have been shown to sensitize tumors with proficient DDR to PARP inhibition [ [12] , [13] , [14] ]. Furthermore, in combination with RT, we and others have previously demonstrated the radiosensitizing potential of combining PI3K and PARP inhibitors [ [15] , [16] , [17] ]. Here, for the first time in a CRC model, we performed a combinatorial analysis of several PARP and PI3K inhibitors to determine the optimally synergistic and radiosensitizing pair.…”

Section: Introductionmentioning

confidence: 99%

Low dose novel PARP-PI3K inhibition via nanoformulation improves colorectal cancer immunoradiotherapy

Landry

DuRoss

Neufeld

et al. 2020

Materials Today Bio

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Multimodal therapy is often used in oncology to overcome dosing limitations and chemoresistance. Recently, combination immunoradiotherapy has shown great promise in a select subset of patients with colorectal cancer (CRC). Furthermore, molecularly targeted agents delivered in tandem with immunotherapy regimens have been suggested to improve treatment outcomes and expand the population of responding patients. In this study, radiation-sensitizing small molecules niraparib (PARP inhibitor) and HS-173 (PI3K inhibitor) are identified as a novel combination that synergistically enhance toxicity and induce immunogenic cell death both in vitro and in vivo in a CRC model. These inhibitors were co-encapsulated in a polymer micelle to overcome solubility limitations while minimizing off-target toxicity. Mice bearing syngeneic colorectal tumors (CT26) were administered these therapeutic micelles in combination with X-ray irradiation and anti-CTLA-4 immunotherapy. This combination led to enhanced efficacy demonstrated by improved tumor control and increased tumor infiltrating lymphocytes. This report represents the first investigation of DNA damage repair inhibition combined with radiation to potentiate anti-CTLA-4 immunotherapy in a CRC model.

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Co-delivery of PARP and PI3K inhibitors by nanoscale metal–organic frameworks for enhanced tumor chemoradiation

Cited by 26 publications

References 57 publications

Chitosan/γ-PGA nanoparticles-based immunotherapy as adjuvant to radiotherapy in breast cancer

Chitosan/γ-PGA nanoparticles-based immunotherapy as adjuvant to radiotherapy in breast cancer

High‐Z Metal–Organic Frameworks for X‐ray Radiation‐Based Cancer Theranostics

Low dose novel PARP-PI3K inhibition via nanoformulation improves colorectal cancer immunoradiotherapy

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