Self-remedied Nanomedicine for Surmounting the Achilles's Heel of Photodynamic Tumor Therapy

Abstract Background: Photodynamic therapy (PDT) has been recognized as a promising tumor treatment for its minimal invasiveness, low side effects and on-demand light controllability. However, the oxygen-dependent PDT could exacerbate tumor hypoxia to upregulate the expression of hypoxia-inducible factor-1α (HIF-1α), which would promote tumor growth and metastasis. Inhibition of HIF-1α activity is very necessary to PDT for effective tumor suppression.Results: Herein, we developed a self-remedied nanomedicine based on a photosensitizer and a HIF-1α inhibitor to surmount the Achilles' heel of PDT for enhanced antitumor efficacy. Specifically, the nanomedicine (designated as CYC-1) was prepared by the self-assembly of Ce6 and YC-1 through π-π stacking and hydrophobic interactions. Carrier-free CYC-1 held an extremely high drug loading rate, uniform size distribution and favorable stability. Compared with free Ce6, CYC-1 exhibited an improved cellular uptake behavior and an enhanced ROS production capability. Besides, CYC-1 had the overwhelming superiority on restraining tumor proliferation over the combined administration of Ce6 and YC-1. More importantly, CYC-1 preferred to accumulate in tumor tissue for efficient PDT by inhibiting the activity of HIF-1α. Ultimately, this YC-1-assistant PDT effectively restrained the tumor growth and caused a low system toxicity. Conclusions: This carrier-free self-remedied strategy overcame the Achilles' heel of PDT on tumor suppression while induced a minimal side effect, which would expedite the development and clinical translation of nanomedicine for PDT against hypoxic tumors.

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Mitochondria-acting carrier-free nanoplatform self-assembled by α-tocopheryl succinate carrying cisplatin for combinational tumor therapy

Regenerative Biomaterials ◽

10.1093/rb/rbab029 ◽

2021 ◽

Vol 8 (4) ◽

Author(s):

Heng Mei ◽

Jing Li ◽

Shengsheng Cai ◽

Xuequan Zhang ◽

Wenqiang Shi ◽

...

Keyword(s):

Drug Loading ◽

Tumor Therapy ◽

Ros Generation ◽

Drug Conjugates ◽

Tocopheryl Succinate ◽

Carrier Free ◽

Negative Surface ◽

Inert Carrier ◽

Self Assembled

Abstract Unsatisfactory drug loading capability, potential toxicity of the inert carrier and the limited therapeutic effect of a single chemotherapy drug are all vital inhibitory factors of carrier-assisted drug delivery systems for chemotherapy. To address the above obstacles, a series of carrier-free nanoplatforms self-assembled by dual-drug conjugates was constructed to reinforce chemotherapy against tumors by simultaneously disrupting intratumoral DNA activity and inhibiting mitochondria function. In this nanoplatform, the mitochondria-targeting small-molecular drug, α-tocopheryl succinate (TOS), firstly self-assembled into nanoparticles, which then were used as the carrier to conjugate cisplatin (CDDP). Systematic characterization results showed that this nanoplatform exhibited suitable particle size and a negative surface charge with good stability in physicochemical environments, as well as pH-sensitive drug release and efficient cellular uptake. Due to the combined effects of reactive oxygen species (ROS) generation by TOS and DNA damage by CDDP, the developed nanoplatform could induce mitochondrial dysfunction and elevated cell apoptosis, resulting in highly efficient anti-tumor outcomes in vitro. Collectively, the combined design principles adopted for carrier-free nanodrugs construction in this study aimed at targeting different intracellular organelles for facilitating ROS production and DNA disruption can be extended to other carrier-free nanodrugs-dependent therapeutic systems.

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Redox-sensitive dimeric camptothecin phosphatidylcholines-based liposomes for improved anticancer efficacy

Nanomedicine ◽

10.2217/nnm-2019-0261 ◽

2019 ◽

Vol 14 (23) ◽

pp. 3057-3074 ◽

Cited By ~ 3

Author(s):

Wei He ◽

Yawei Du ◽

Wenya Zhou ◽

Chen Yao ◽

Xinsong Li

Keyword(s):

Drug Loading ◽

Tumor Therapy ◽

Anticancer Activities ◽

Uniform Size ◽

Anticancer Efficacy ◽

Liposomal System ◽

Rapid Release ◽

Clinical Potential

Aim: A redox-triggered camptothecin (CPT) liposomal system was developed for an improved clinical potential in tumor therapy. Materials & methods: CPT–phosphorylcholine conjugates (CPT–SS–GPCs: CPT–SS–3–GPC and CPT–SS–11–GPC) were synthesized by conjugating CPT to glycerylphosphorylcholine via disulfide bond linker. CPT–SS–GPCs could be assembled into liposomes. Different in vitro and in vivo analyses were used to evaluate the anticancer activities of CPT–SS–GPCs. Results: CPT–SS–GPCs liposomes exhibited extremely high drug loading and uniform size of 150–200 nm. Moreover, the rapid release of parent CPT in reductive condition and high cellular uptake of CPT–SS–GPCs liposomes were observed. At last, in vitro and in vivo anticancer assay showed the enhanced efficacy of CPT–SS–GPCs liposomes. Conclusion: Redox-triggered CPT–SS–GPC liposomes have great potential in tumor therapy.

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TAp73 opposes tumor angiogenesis by promoting hypoxia-inducible factor 1α degradation

10.31234/osf.io/v24zc ◽

2020 ◽

Author(s):

Lungwani Muungo

Keyword(s):

Cancer Progression ◽

Hypoxia Inducible Factor ◽

Tumor Hypoxia ◽

Human Lung Cancer ◽

Regulatory Subunit ◽

Patients With Cancer ◽

Hypoxia Inducible Factor 1 ◽

Chemically Induced ◽

Induced Tumors ◽

Patient Prognosis

Tumor hypoxia and hypoxia-inducible factor 1 (HIF-1) activationare associated with cancer progression. Here, we demonstrate thatthe transcription factor TAp73 opposes HIF-1 activity through anontranscriptional mechanism, thus affecting tumor angiogenesis.TAp73-deficient mice have an increased incidence of spontaneousand chemically induced tumors that also display enhanced vascularization.Mechanistically, TAp73 interacts with the regulatory subunit(α) of HIF-1 and recruits mouse double minute 2 homolog intothe protein complex, thus promoting HIF-1α polyubiquitination andconsequent proteasomal degradation in an oxygen-independentmanner. In human lung cancer datasets, TAp73 strongly predictsgood patient prognosis, and its expression is associated with lowHIF-1 activation and angiogenesis. Our findings, supported by invivo and clinical evidence, demonstrate a mechanism for oxygenindependentHIF-1 regulation, which has important implicationsfor individualizing therapies in patients with cancer.

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Anticancer Activity of Natural Flavonoids: Inhibition of HIF-1α Signaling Pathway

Current Organic Chemistry ◽

10.2174/1385272823666191203122030 ◽

2020 ◽

Vol 23 (26) ◽

pp. 2945-2959 ◽

Cited By ~ 1

Author(s):

Xiangping Deng ◽

Yijiao Peng ◽

Jingduo Zhao ◽

Xiaoyong Lei ◽

Xing Zheng ◽

...

Keyword(s):

Transcription Factor ◽

Secondary Metabolites ◽

Anticancer Agents ◽

Hypoxia Inducible Factor ◽

Tumor Hypoxia ◽

Pharmacological Activities ◽

Hypoxia Inducible Factor 1 ◽

The Past ◽

Low Toxicity ◽

Tumor Blood Vessels

Rapid tumor growth is dependent on the capability of tumor blood vessels and glycolysis to provide oxygen and nutrients. Tumor hypoxia is a common characteristic of many solid tumors, and it essentially happens when the growth of the tumor exceeds the concomitant angiogenesis. Hypoxia-inducible factor 1 (HIF-1) as the critical transcription factor in hypoxia regulation is activated to adapt to this hypoxia situation. Flavonoids, widely distributed in plants, comprise many polyphenolic secondary metabolites, possessing broadspectrum pharmacological activities, including their potentiality as anticancer agents. Due to their low toxicity, intense efforts have been made for investigating natural flavonoids and their derivatives that can be used as HIF-1α inhibitors for cancer therapy during the past few decades. In this review, we sum up the findings concerning the inhibition of HIF-1α by natural flavonoids in the last few years and propose the idea of designing tumor vascular and glycolytic multi-target inhibitors with HIF-1α as one of the targets.

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Hyaluronan based Multifunctional Nano-carriers for Combination Cancer Therapy

Current Topics in Medicinal Chemistry ◽

10.2174/1568026620666200922113846 ◽

2020 ◽

Vol 20 ◽

Author(s):

Menghan Gao ◽

Hong Deng ◽

Weiqi Zhang

Keyword(s):

Cancer Therapy ◽

Combination Therapy ◽

Cancer Cells ◽

Drug Loading ◽

Tumor Therapy ◽

Drug Carriers ◽

Functional Sites ◽

Therapeutic Modalities ◽

Combination Cancer Therapy ◽

Targeting Strategy

: Hyaluronan (HA) is a natural linear polysaccharide that has excellent hydrophilicity, biocompatibility, biodegradability, and low immunogenicity, making it one of the most attractive biopolymers used for biomedical researches and applications. Due to the multiple functional sites on HA and its intrinsic affinity for CD44, a receptor highly expressed on various cancer cells, HA has been widely engineered to construct different drug-loading nanoparticles (NPs) for CD44- targeted anti-tumor therapy. When a cocktail of drugs is co-loaded in HA NP, a multifunctional nano-carriers could be obtained, which features as a highly effective and self-targeting strategy to combat the cancers with CD44 overexpression. The HA-based multidrug nano-carriers can be a combination of different drugs, various therapeutic modalities, or the integration of therapy and diagnostics (theranostics). Up to now, there are many types of HA-based multidrug nano-carriers constructed by different formulation strategies including drug co-conjugates, micelles, nano-gels and hybrid NP of HA and so on. This multidrug nano-carrier takes the full advantages of HA as NP matrix, drug carriers and targeting ligand, representing a simplified and biocompatible platform to realize the targeted and synergistic combination therapy against the cancers. In this review, recent progresses about HA-based multidrug nano-carriers for combination cancer therapy are summarized and its potential challenges for translational applications have been discussed.

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Secretogranin II impairs tumor growth and angiogenesis by promoting degradation of hypoxia‐inducible factor‐1α in colorectal cancer

Molecular Oncology ◽

10.1002/1878-0261.13044 ◽

2021 ◽

Author(s):

Chao Fang ◽

Lei Dai ◽

Cun Wang ◽

Chuanwen Fan ◽

Yongyang Yu ◽

...

Keyword(s):

Colorectal Cancer ◽

Tumor Growth ◽

Hypoxia Inducible Factor ◽

Hypoxia Inducible Factor 1Α ◽

Secretogranin Ii

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Let-7f miRNA regulates SDF-1α- and hypoxia-promoted migration of mesenchymal stem cells and attenuates mammary tumor growth upon exosomal release

Cell Death and Disease ◽

10.1038/s41419-021-03789-3 ◽

2021 ◽

Vol 12 (6) ◽

Author(s):

Virginia Egea ◽

Kai Kessenbrock ◽

Devon Lawson ◽

Alexander Bartelt ◽

Christian Weber ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Tumor Growth ◽

Molecular Mechanisms ◽

Hypoxia Inducible Factor ◽

Human Mesenchymal Stem Cells ◽

Target Cells ◽

Autophagic Flux ◽

Stromal Cell Derived Factor

AbstractBone marrow-derived human mesenchymal stem cells (hMSCs) are recruited to damaged or inflamed tissues where they contribute to tissue repair. This multi-step process involves chemokine-directed invasion of hMSCs and on-site release of factors that influence target cells or tumor tissues. However, the underlying molecular mechanisms are largely unclear. Previously, we described that microRNA let-7f controls hMSC differentiation. Here, we investigated the role of let-7f in chemotactic invasion and paracrine anti-tumor effects. Incubation with stromal cell-derived factor-1α (SDF-1α) or inflammatory cytokines upregulated let-7f expression in hMSCs. Transfection of hMSCs with let-7f mimics enhanced CXCR4-dependent invasion by augmentation of pericellular proteolysis and release of matrix metalloproteinase-9. Hypoxia-induced stabilization of the hypoxia-inducible factor 1 alpha in hMSCs promoted cell invasion via let-7f and activation of autophagy. Dependent on its endogenous level, let-7f facilitated hMSC motility and invasion through regulation of the autophagic flux in these cells. In addition, secreted let-7f encapsulated in exosomes was increased upon upregulation of endogenous let-7f by treatment of the cells with SDF-1α, hypoxia, or induction of autophagy. In recipient 4T1 tumor cells, hMSC-derived exosomal let-7f attenuated proliferation and invasion. Moreover, implantation of 3D spheroids composed of hMSCs and 4T1 cells into a breast cancer mouse model demonstrated that hMSCs overexpressing let-7f inhibited tumor growth in vivo. Our findings provide evidence that let-7f is pivotal in the regulation of hMSC invasion in response to inflammation and hypoxia, suggesting that exosomal let-7f exhibits paracrine anti-tumor effects.

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Tumor hypoxia induces nuclear paraspeckle formation through HIF-2α dependent transcriptional activation of NEAT1 leading to cancer cell survival

Oncogene ◽

10.1038/onc.2014.378 ◽

2014 ◽

Vol 34 (34) ◽

pp. 4482-4490 ◽

Cited By ~ 118

Author(s):

H Choudhry ◽

A Albukhari ◽

M Morotti ◽

S Haider ◽

D Moralli ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cell ◽

Transcriptional Activation ◽

Cellular Proliferation ◽

Hypoxia Inducible Factor ◽

Tumor Hypoxia ◽

Transcriptional Response ◽

Clonogenic Survival ◽

Breast Cancer Cell Lines ◽

Transcriptional Responses

Abstract Activation of cellular transcriptional responses, mediated by hypoxia-inducible factor (HIF), is common in many types of cancer, and generally confers a poor prognosis. Known to induce many hundreds of protein-coding genes, HIF has also recently been shown to be a key regulator of the non-coding transcriptional response. Here, we show that NEAT1 long non-coding RNA (lncRNA) is a direct transcriptional target of HIF in many breast cancer cell lines and in solid tumors. Unlike previously described lncRNAs, NEAT1 is regulated principally by HIF-2 rather than by HIF-1. NEAT1 is a nuclear lncRNA that is an essential structural component of paraspeckles and the hypoxic induction of NEAT1 induces paraspeckle formation in a manner that is dependent upon both NEAT1 and on HIF-2. Paraspeckles are multifunction nuclear structures that sequester transcriptionally active proteins as well as RNA transcripts that have been subjected to adenosine-to-inosine (A-to-I) editing. We show that the nuclear retention of one such transcript, F11R (also known as junctional adhesion molecule 1, JAM1), in hypoxia is dependent upon the hypoxic increase in NEAT1, thereby conferring a novel mechanism of HIF-dependent gene regulation. Induction of NEAT1 in hypoxia also leads to accelerated cellular proliferation, improved clonogenic survival and reduced apoptosis, all of which are hallmarks of increased tumorigenesis. Furthermore, in patients with breast cancer, high tumor NEAT1 expression correlates with poor survival. Taken together, these results indicate a new role for HIF transcriptional pathways in the regulation of nuclear structure and that this contributes to the pro-tumorigenic hypoxia-phenotype in breast cancer.

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