While IL-2 can potently activate both NK and T cells, its short in vivo half-life, severe toxicity, and propensity to amplify Treg cells are major barriers that prevent IL-2 from being widely used ...for cancer therapy. In this study, we construct a recombinant IL-2 immunocytokine comprising a tumor-targeting antibody (Ab) and a super mutant IL-2 (sumIL-2) with decreased CD25 binding and increased CD122 binding. The Ab-sumIL2 significantly enhances antitumor activity through tumor targeting and specific binding to cytotoxic T lymphocytes (CTLs). We also observe that pre-existing CTLs within the tumor are sufficient and essential for sumIL-2 therapy. This next-generation IL-2 can also overcome targeted therapy-associated resistance. In addition, preoperative sumIL-2 treatment extends survival much longer than standard adjuvant therapy. Finally, Ab-sumIL2 overcomes resistance to immune checkpoint blockade through concurrent immunotherapies. Therefore, this next-generation IL-2 reduces toxicity while increasing TILs that potentiate combined cancer therapies.
Since the discovery of metal nanoparticles (NPs) in the 1960s, unknown toxicity, cost and the ethical hurdles of research in humans have hindered the translation of these NPs to clinical use. In this ...work, we demonstrate that Pt NPs with protein coronas are generated in vivo in human blood when a patient is treated with cisplatin. These self-assembled Pt NPs form rapidly, accumulate in tumors, and remain in the body for an extended period of time. Additionally, the Pt NPs are safe for use in humans and can act as anti-cancer agents to inhibit chemotherapy-resistant tumor growth by consuming intracellular glutathione and activating apoptosis. The tumor inhibitory activity is greatly amplified when the Pt NPs are loaded in vitro with the chemotherapeutic drug, daunorubicin, and the formulation is effective even in daunorubicin-resistant models. These in vivo-generated metal NPs represent a biocompatible drug delivery platform for chemotherapy resistant tumor treatment.
Hypoxia is a hostile hallmark of most solid tumors, which often leads to multidrug resistance (MDR) and causes the failure of chemotherapy. Hypoxia also promotes epithelial–mesenchymal transition ...(EMT), leading to acceleration of tumor metastasis. Many chemotherapeutic drugs can further exacerbate hypoxia and thus promote metastasis. Therefore, relieving hypoxia is necessary for chemotherapy to inhibit both MDR and EMT. Herein, highly stable cerasomal perfluorocarbon nanodroplets with an atomic layer of polyorganosiloxane surface and pH-sensitive tumor-targeting peptide (D-vPCs-O2) were fabricated to co-deliver oxygen and therapeutic drug, doxorubicin. High-intensity focused ultrasound (HIFU) was utilized to trigger the co-release of doxorubicin and oxygen and simultaneously enhance ultrasound imaging, therefore achieving imaging-guided drug delivery. Mild-temperature HIFU (M-HIFU) not only triggered oxygen release from nanodroplets but also slightly elevated tumor temperature to accelerate tumor blood flow. The oxygen release and temperature elevation jointly relieved tumor hypoxia and alleviated MDR, which greatly enhanced the drug therapeutic efficacy as compared to clinically used doxorubicin and Doxil. Overall side effects were also largely reduced owing to the ultrastable drug loading of cerasome. The improvement of insufficient chemotherapy and the relief of tumor hypoxia corporately down-regulated TGF-β1, leading to the alleviation of EMT, and therefore significantly inhibited tumor metastasis. When “D-vPCs-O2 + M-HIFU” was utilized as a neoadjuvant chemotherapy, nanodroplets down-regulated heat shock proteins, reducing tumor relapse after the high-temperature HIFU (H-HIFU)-mediated hyperthermia ablation. The chemo-hyperthermia therapy totally eradicated tumors without any relapse or metastasis, providing a promising way to treat the triple-negative breast cancer, which is highly malignant, easily metastatic, and lacks effective treatments.
Circular RNAs (circRNAs) have gained growing attention in participating in various biological processes and referring to multiply kinds of diseases. Although differentially expressed circRNA ...profiling in Alzheimer's disease (AD) has been established, little is known about the precise characteristic and functions of key circRNAs with direct relevance to AD in gene expression and disease-related cognition. Herein, we screened and identified circCwc27 as a novel circRNA implicated in AD. CircCwc27 was a neuronal-enriched circRNA that abundantly expressed in the brain and significantly upregulated in AD mice and patients. Knockdown of circCwc27 markedly improved AD-related pathological traits and ameliorated cognitive dysfunctions. Mechanistically, we excluded the miRNA decoy mechanism and focused on the important function of circRNA-RNA-binding protein (RBP) interaction in AD. CircCwc27 directly bound to purine-rich element-binding protein A (Pur-α), increased retention of cytoplasmic Pur-α, and suppressed Pur-α recruitment to the promoters of a cluster of AD genes, including amyloid precursor protein (APP), dopamine receptor D1 (Drd1), protein phosphatase 1, regulatory inhibitor subunit1B (Ppp1r1b), neurotrophic tyrosine kinase, receptor, type 1 (Ntrk1), and LIM homeobox 8 (Lhx8). Downregulation of circCwc27 enhanced the affinity of Pur-α binding to these promoters, leading to altered transcription of Pur-α targets. Moreover, Pur-α overexpression largely phenocopied circCwc27 knockdown in preventing Aβ deposition and cognitive decline. Together, our findings suggest significant functional consequences of a circRNA-protein interaction, that circCwc27, by associating with the regulatory protein Pur-α, may act as a crucial player in AD pathogenesis and represent a promising AD therapeutic target with clinical translational potential.
Alzheimer's disease (AD) is the most common neurodegenerative disease in the elderly worldwide. However, the complexity of AD pathogenesis leads to discrepancies in the understanding of this disease, ...and may be the main reason for the failure of AD drug development. Fortunately, many ongoing preclinical and clinical studies will continually open up avenues to unravel disease mechanisms and guide strategies for AD diagnosis and drug development. For example, immunotherapeutic strategies targeting amyloid-β (Aβ) and tau proteins were once deemed almost certainly effective in clinical treatment due to the excellent preclinical results. However, the repeated failures of clinical trials on vaccines and humanized anti-Aβ and anti-tau monoclonal antibodies have resulted in doubts on this strategy. Recently, a new anti-Aβ monoclonal antibody (Aducanumab) has been approved by the US Food and Drug Administration, which brings us back to the realization that immunotherapy strategies targeting Aβ may be still promising. Meanwhile, immunotherapies based on other targets such as tau, microglia and gut-brain axis are also under development. Further research is still needed to clarify the forms and epitopes of targeted proteins to improve the accuracy and effectiveness of immunotherapeutic drugs. In this review, we focus on the immunotherapies based on Aβ, tau and microglia and their mechanisms of action in AD. In addition, we present up-to-date advances and future perspectives on immunotherapeutic strategies for AD.
Targeting receptors overexpressed on cancer cells with radiolabeled peptides has become a crucial aspect of molecular imaging in oncology. Small peptides offer favorable characteristics for tumor ...targeting with minimal side effects and toxicity owing to their small size and simple radiolabeling protocols. Among them, somatostatin analogs have received regulatory approval for the diagnosis and treatment of neuroendocrine tumors. Cyclic RGD (Arg‐Gly‐Asp) peptides, bombesin analogs, and glucagon‐like peptide‐1 analogs are currently under development and/or undergoing clinical trials. The most used radionuclides for tumor imaging include 99mTc and 111In for single‐photon emission computed tomography, 68Ga and 18F for positron emission tomography. This review highlights the clinical potential and future prospects of 99mTc‐labeled peptides for tumor imaging.
The composition of a 99mTc‐labeled peptide radiopharmaceutical probe includes the radionuclide (99mTc), chelating agents (6‐hydrazinonicotinic acid, 2 mercaptoacetylglycylglycyl/mercaptoacetyltriglycine, N,N′‐bis(2‐methyl‐2‐mercaptopropyl)ethylenediamine, ethylene dicysteine, N3S, etc.), peptides (peptides targeting tumor receptors such as somatostatin receptor, Integrin Receptors, human epidermal growth factor receptor 2, gastrin‐releasing peptide receptor, glucagon‐like peptide‐1 Receptor, C‐X‐C chemokine receptor‐type 4, etc.), and pharmacokinetics modification linkers (polyethylene glycol, Glycosyl, Lipid, etc.). These components work in concert to impart targeting capabilities, radioactivity, and imaging capabilities to the labeled molecular probe, making it suitable for molecular imaging in nuclear medicine.
Alzheimer's disease (AD) is a complicated neurodegenerative disease and therefore addressing multiple targets simultaneously has been believed as a promising therapeutic strategy against AD. α7 ...nicotinic acetylcholine receptor (nAChR), which plays an important role in improving cognitive function and alleviating neuroinflammation in central nervous system (CNS), has been regarded as a potential target in the treatment of AD. However, the regulation of α7 nAChR at post‐transcriptional level in mammalian brain remains largely speculated. Herein, we uncovered a novel post‐transcriptional regulatory mechanism of α7 nAChR expression in AD and further demonstrated that miR‐98‐5p suppressed α7 nAChR expression through directly binding to the 3′UTR of mRNA. Knockdown of miR‐98‐5p activated Ca2+ signaling pathway and consequently reversed cognitive deficits and Aβ burden in APP/PS1 mice. Furthermore, miR‐98‐5p downregulation increased α7 nAChR expression, and ameliorated neuroinflammation via inhibiting NF‐κB pathway and upregulating Nrf2 target genes. Our findings illustrate a prominent regulatory role of miR‐98‐5p in targeting inflammation and cognition, and provide an insight into the potential of miR‐98‐5p/α7 nAChR axis as a novel therapeutic strategy for AD.
Abstract
Gadolinium (Gd
3+
)-coordinated texaphyrin (Gd-Tex) is a promising radiosensitizer that entered clinical trials, but temporarily fails largely due to insufficient radiosensitization ...efficacy. Little attention has been given to using nanovesicles to improve its efficacy. Herein, Gd-Tex is transformed into building blocks “Gd-Tex-lipids” to self-assemble nanovesicles called Gd-nanotexaphyrins (Gd-NTs), realizing high density packing of Gd-Tex in a single nanovesicle and achieving high Gd-Tex accumulation in tumors. To elucidate the impact of O
2
concentration on Gd-Tex radiosensitization, myoglobin (Mb) is loaded into Gd-NTs (Mb@Gd-NTs), resulting in efficient relief of tumor hypoxia and significant enhancement of Gd-Tex radiosensitization, eventually inducing the obvious long-term antitumor immune memory to inhibit tumor recurrence. In addition to Gd
3+
, the versatile Mb@Gd-NTs can also chelate
177
Lu
3+
(Mb@
177
Lu/Gd-NTs), enabling SPECT/MRI dual-modality imaging for accurately monitoring drug delivery in real-time. This “one-for-all” nanoplatform with the capability of chelating various trivalent metal ions exhibits broad clinical application prospects in imaging-guided radiosensitization therapy.
Abstract
Background
Due to the temporal and spatial heterogeneity of human epidermal growth factor receptor 2 (HER2) expression in breast tumors, immunohistochemistry (IHC) cannot accurately reflect ...the HER2 status in real time, which may cause misguided treatment decisions. HER2-specific imaging can noninvasively determine HER2 status in primary and metastatic tumors. In this study
,
HER2 expression in breast cancer patients was determined in vivo by SPECT/CT of
99m
Tc-HP-Ark2, comparing with PET/CT of
18
F-FDG lesion by lesion.
Methods
A novel HER2-targeted peptide probe
99m
Tc-HP-Ark2 was constructed. Biodistribution and nanoScan SPECT/CT imaging were performed in mice models. The correlation between the quantified tumor uptake and HER2 expression in tumor cells was analyzed. In the pilot clinical study, a total of 34 breast cancer patients (mean age ± SD: 49 ± 10 y) suspected of having breast cancer according to mammography or ultrasonography were recruited at Peking Union Medical College Hospital, and
99m
Tc-HP-Ark2 SPECT/CT and
18
F-FDG PET/CT were carried out with IHC and fluorescence in situ hybridization as validation.
Results
Small animal SPECT/CT of
99m
Tc-HP-Ark2 clearly identified tumors with different HER2 expression. The quantified tumor uptake and tumor HER2 expression showed a significant linear correlation (r = 0.932, P < 0.01). Among the 36 primary lesions in the 34 patients, when IHC (2 +) or IHC (3 +) was used as the positive evaluation criterion,
99m
Tc-HP-Ark2 SPECT/CT imaging with a tumor-to-background ratio of 1.44 as the cutoff value reflected the HER2 status with sensitivity of 89.5% (17/19), specificity of 88.2% (15/17) and accuracy of 88.9% (32/36), while the
18
F-FDG PET/CT showed sensitivity of 78.9% (15/19), specificity of 70.6% (12/17) and accuracy of 75.0% (27/36). In particular, 100% of IHC (3 +) tumors were all identified by
99m
Tc-HP-Ark2 SPECT/CT imaging.
Conclusion
99m
Tc-HP-Ark2 SPECT/CT can provide a specific, noninvasive evaluation of HER2 expression in breast cancer, showing great potential to guide HER2-targeted therapies in clinical practice.
ClinicalTrials.gov Trial registration: NCT04267900. Registered 11th February 2020. Retrospectively registered,
https://www.clinicaltrials.gov/ct2/results?pg=1&load=cart&id=NCT04267900
.
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