Cyclopamine disrupts tumor extracellular matrix and improves the distribution and efficacy of nanotherapeutics in pancreatic cancer

Zhang, Bo; Jiang, Ting; Shen, Shun; She, Xiaojian; Tuo, Yanyan; Hu, Yu; Pang, Zhiqing; Jiang, Xinguo

doi:10.1016/j.biomaterials.2016.06.048

Cited by 71 publications

(45 citation statements)

References 40 publications

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“…After losartan treatment, the tumor penetration of Doxil was obviously enhanced due to the losartan‐induced collagen fiber disruption . Similarly, cyclopamine pretreatment disrupted the extracellular level of fibronectins and potentially reduced the obstacles to intratumoral diffusion of nanoparticles, thus favoring the penetration of 115 nm nanoparticles . Recently, a MMP‐2‐sensitive liposome with pirfenidone was designed to suppress the expression of multiple ECM components, including collagen I, fibronectin, versican, and tenascin C, thereby leading to a significant increase in the penetration of gemcitabine into tumor tissue ( Figure A) …”

Section: Remodeling Of Tumor Stromal Microenvironmentsmentioning

confidence: 99%

Rational Design of Nanoparticles with Deep Tumor Penetration for Effective Treatment of Tumor Metastasis

Zhang

Wang

Tan

et al. 2018

Adv Funct Materials

132

106

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The limited penetration of nanoparticles in primary tumors and metastases remains a great challenge for effective treatment of tumor metastasis. This review outlines the current approaches and summarizes the rational design of nanoparticles with deep tumor penetration capacity for anti-metastasis treatment. There are two ways to achieve better tumor penetration; through rational regulation of the physicochemical properties of nanoparticles and through remodeling of the tumor microenvironment, including the tumor vasculature and stromal environment. Moreover, biomimetic strategies that integrate the advantages of nanoparticles and metastasis-homing molecules during cancer cell metastasis are discussed. These efforts have led to promising results in facilitating intratumoral permeation of various nanoparticles to enhance antitumor effects. The considerations and some feasible future directions for deep tumor penetration strategies are proposed to improve tumor metastasis therapies.

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Section: Remodeling Of Tumor Stromal Microenvironmentsmentioning

confidence: 99%

Rational Design of Nanoparticles with Deep Tumor Penetration for Effective Treatment of Tumor Metastasis

Zhang

Wang

Tan

et al. 2018

Adv Funct Materials

132

106

View full text Add to dashboard Cite

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“…showed that the inhibition of Hh signaling pathway using IPI-926 improved gemcitabine delivery to pancreatic cancer KPC mouse model [25]. Similarly, the Jiang group demonstrated that CYP disrupts the ECM and enhances the delivery and efficacy of nanoparticles in pancreatic cancer [10]. …”

Section: Discussionmentioning

confidence: 99%

“…Cyclopamine (CYP) is a natural steroidal alkaloid, which can inhibit the Hh signaling pathway by blocking the 12-transmembrane protein smoothened (Smo) that inactivates the transcription factor glioma-associated oncogene family zinc finger-1 (GLI-1) [10]. As a result, CYP downregulates the target genes that are responsible for dense desmoplastic formation.…”

Section: Introductionmentioning

confidence: 99%

Coadministration of Polymeric Conjugates of Docetaxel and Cyclopamine Synergistically Inhibits Orthotopic Pancreatic Cancer Growth and Metastasis

2018

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Purpose The aim of this study was to determine whether co-administration of hedgehog (Hh) pathway inhibitor cyclopamine (CYP) and microtubule stabilizer docetaxel (DTX) as polymer-drug conjugates, methoxy poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylenecarbonate-graft-dodecanol-graft-cyclopamine) (P-CYP) and methoxy poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propyl-ene carbonate-graft-dodecanol-graft-docetaxel) (P-DTX) could synergistically inhibit orthotopic pancreatic tumor growth in NSG mice. Methods P-DTX and P-CYP were synthesized from mPEG-b-PCC through carbodiimide coupling reaction and characterized by 1H–NMR. The micelles were prepared by film hydration and particle size was measured by dynamic light scattering (DLS). Cytotoxicity, apoptosis and cell cycle analysis of P-DTX and P-CYP were evaluated in MIA PaCa-2 cells. In vivo efficacy of P-DTX and P-CYP were evaluated in NSG mice bearing MIA PaCa-2 cells derived orthotopic pancreatic tumor. Results P-CYP and P-DTX self-assembled into micelles of <90 nm and their combination therapy efficiently inhibited the proliferation of MIA PaCa-2 cells, induced apoptosis and cell cycle arrest at M-phase more efficiently than P-CYP and P-DTX monotherapies. Furthermore, the combination therapy of P-CYP and P-DTX significantly reduced Hh component expression compared to P-CYP alone as determined by Western blot analysis. Lastly, the combination therapy induced greater inhibition of orthotopic pancreatic tumor growth in NSG mice compared to their monotherapies. Conclusion Combination of polymer conjugated anticancer drug (P-DTX) with polymer conjugated Hh inhibitor (P-CYP) enhanced pancreatic cancer cell killing, apoptosis as well as in vivo tumor growth inhibition with no obvious toxicities.

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“…Wang et al developed a small interfering RNA (siRNA)‐loaded polymeric nanoparticles capable of tumor‐specifically inhibition of Nogo‐B receptors in both tumor and endothelial cells, inducing vessel normalization and inhibiting tumor metastasis. In addition, because the thick ECM can compress tumor vessels and lead to the irregular distribution of vessels within tumors, Jiang et al and Liu et al suggest that decompressing the ECM with hyaluronidase or a cyclopamine inhibitor can normalize tumor vasculature and improve the efficacy of nanoparticle‐based chemotherapy and photodynamic therapy …”

Section: Nanoparticle‐mediated Tumor Vessel Targetingmentioning

confidence: 99%

Modulating the tumor microenvironment with new therapeutic nanoparticles: A promising paradigm for tumor treatment

Zhang

et al. 2019

Medicinal Research Reviews

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To better make nanomedicine entering the clinic, developing new rationally designed nanotherapeutics with a deeper understanding of tumor biology is required. The tumor microenvironment is similar to the inflammatory response in a healing wound, the milieu of which promotes tumor cell invasion and metastasis. Successful targeting of the microenvironmental components with effective nanotherapeutics to modulate the tumor microvessels or restore the homeostatic mechanisms in the tumor stroma will offer new hope for cancer treatment. We here highlight the progress in constructing nanotherapeutics to target or modulate the tumor microenvironment. We discuss the factors necessary for nanomedicines to become a new paradigm in cancer therapy, including the selection of drugs and therapeutic targets, controllable synthesis, and tempo-spatial drug release. K E Y W O R D S drug delivery, nanotherapeutics, therapeutic targets, tumor microenvironment Guangjun Nie and Suping Li are co-corresponding authors.Yinlong Zhang and Shih-Hsin Ho contributed equally to this work.

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Cyclopamine disrupts tumor extracellular matrix and improves the distribution and efficacy of nanotherapeutics in pancreatic cancer

Cited by 71 publications

References 40 publications

Rational Design of Nanoparticles with Deep Tumor Penetration for Effective Treatment of Tumor Metastasis

Rational Design of Nanoparticles with Deep Tumor Penetration for Effective Treatment of Tumor Metastasis

Coadministration of Polymeric Conjugates of Docetaxel and Cyclopamine Synergistically Inhibits Orthotopic Pancreatic Cancer Growth and Metastasis

Modulating the tumor microenvironment with new therapeutic nanoparticles: A promising paradigm for tumor treatment

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