Co-reporter:Hongmin Chen;Xilin Sun;Geoffrey D. Wang;Koichi Nagata;Zhonglin Hao;Andrew Wang;Zibo Li;Baozhong Shen
Materials Horizons (2014-Present) 2017 vol. 4(Issue 6) pp:1092-1101
Publication Date(Web):2017/10/30
DOI:10.1039/C7MH00442G
Using X-rays as the irradiation source, a photodynamic therapy process can be initiated in deep tissues. This technology, referred to as X-ray induced PDT, or X-PDT, holds great potential to treat tumors in internal organs. To this end, one question is how to navigate the treatment of tumors with accuracy using external irradiation. Herein we address this issue using a novel LiGa5O8:Cr (LGO:Cr)-based nanoscintillator, which emits persistent, near-infrared X-ray luminescence. This permits deep-tissue optical imaging that can be employed to guide irradiation. Specifically, we encapsulated LGO:Cr nanoparticles and a photosensitizer, 2,3-naphthalocyanine, into mesoporous silica nanoparticles. The nanoparticles were conjugated with cetuximab and systemically injected into H1299 orthotopic non-small cell lung cancer tumor models. The nanoconjugates can efficiently accumulate in tumors in the lungs, confirmed by monitoring the X-ray luminescence from LGO:Cr. Guided by the imaging, external irradiation was applied, leading to efficient tumor suppression while minimally affecting normal tissues. To the best of our knowledge, the present study is the first to demonstrate, with systematically injected nanoparticles, that X-PDT can suppress the growth of deep-seated tumors. The imaging guidance is also new to X-PDT, and is significant to the further transformation of the technology.
Co-reporter:Zipeng Zhen, Wei Tang, Mengzhe Wang, Shiyi Zhou, Hui WangZhanhong Wu, Zhonglin Hao, Zibo Li, Lin Liu, Jin Xie
Nano Letters 2017 Volume 17(Issue 2) pp:
Publication Date(Web):December 28, 2016
DOI:10.1021/acs.nanolett.6b04150
Carcinoma-associated fibroblasts (CAFs) are found in many types of cancer and play an important role in tumor growth and metastasis. Fibroblast-activation protein (FAP), which is overexpressed on the surface of CAFs, has been proposed as a universal tumor targeting antigen. However, recent studies show that FAP is also expressed on multipotent bone marrow stem cells. A systematic anti-FAP therapy may lead to severe side effects and even death. Hence, there is an urgent need of a therapy that can selectively kill CAFs without causing systemic toxicity. Herein we report a nanoparticle-based photoimmunotherapy (nano-PIT) approach that addresses the need. Specifically, we exploit ferritin, a compact nanoparticle protein cage, as a photosensitizer carrier, and we conjugate to the surface of ferritin a FAP-specific single chain variable fragment (scFv). With photoirradiation, the enabled nano-PIT efficiently eliminates CAFs in tumors but causes little damage to healthy tissues due to the localized nature of the treatment. Interestingly, while not directly killing cancer cells, the nano-PIT caused efficient tumor suppression in tumor-bearing immunocompetent mice. Further investigations found that the nano-PIT led to suppressed C–X–C motif chemokine ligand 12 (CXCL12) secretion and extracellular matrix (ECM) deposition, both of which are regulated by CAFs in untreated tumors and mediate T cell exclusion that prevents physical contact between T cells and cancer cells. By selective killing of CAFs, the nano-PIT reversed the effect, leading to significantly enhanced T cell infiltration, followed by efficient tumor suppression. Our study suggests a new and safe CAF-targeted therapy and a novel strategy to modulate tumor microenvironment (TME) for enhanced immunity against cancer.Keywords: carcinoma-associated fibroblast; cytotoxic T cells; fibroblast-activation protein; immunotherapy; Photodynamic therapy;
Co-reporter:Wei Tang;Zipeng Zhen;Mengzhe Wang;Hui Wang;Yen-Jun Chuang;Weizhong Zhang;Geoffrey D Wang;Trever Todd;Taku Cowger;Hongmin Chen;Lin Liu;Zibo Li
Advanced Functional Materials 2016 Volume 26( Issue 11) pp:1757-1768
Publication Date(Web):
DOI:10.1002/adfm.201504803
Photodynamic therapy (PDT) is a promising treatment modality for cancer management. So far, most PDT studies have focused on delivery of photosensitizers to tumors. O2, another essential component of PDT, is not artificially delivered but taken from the biological milieu. However, cancer cells demand a large amount of O2 to sustain their growth and that often leads to low O2 levels in tumors. The PDT process may further potentiate the oxygen deficiency, and in turn, adversely affect the PDT efficiency. In the present study, a new technology called red blood cell (RBC)-facilitated PDT, or RBC-PDT, is introduced that can potentially solve the issue. As the name tells, RBC-PDT harnesses erythrocytes, an O2 transporter, as a carrier for photosensitizers. Because photosensitizers are adjacent to a carry-on O2 source, RBC-PDT can efficiently produce 1O2 even under low oxygen conditions. The treatment also benefits from the long circulation of RBCs, which ensures a high intraluminal concentration of photosensitizers during PDT and hence maximizes damage to tumor blood vessels. When tested in U87MG subcutaneous tumor models, RBC-PDT shows impressive tumor suppression (76.7%) that is attributable to the codelivery of O2 and photosensitizers. Overall, RBC-PDT is expected to find wide applications in modern oncology.
Co-reporter:Hongmin Chen;Geoffrey D. Wang;Xilin Sun;Trever Todd;Fan Zhang;Baozhong Shen
Advanced Functional Materials 2016 Volume 26( Issue 22) pp:3973-3982
Publication Date(Web):
DOI:10.1002/adfm.201504177
Gd-encapsulated carbonaceous dots (Gd@C-dots) hold great potential in clinical applications as a novel type of T1 contrast agent for magnetic resonance imaging (MRI). However, current synthetic methods require multiple purification steps due to poor size control, making them unsuitable for high throughput. Herein, a novel, mesoporous silica nanoparticle (MSN)-templated method for the size-controlled synthesis of Gd@C-dots is reported. Briefly, MSNs nanoreactors of different pore sizes are loaded with Gd precursors. Upon calcination, carbon layers are grown around the Gd cations. The spatial restraint of the silica cavity facilitates size control of the produced Gd@C-dots. Specifically, using 3, 7, and 11 nm MSNs as templates allows the synthesis of 3.0, 7.4, and 9.6 nm Gd@C-dots, respectively. A significant size impact on the magnetic and optical properties of the nanoparticles is shown, with the smallest Gd@C-dots showing the highest r1 relaxivity (10 mM−1 s−1) and fluorescence quantum yield (30.2%). The 3.0-nm Gd@C-dots were then conjugated with a tumor-targeting ligand, c(RGDyK), and injected into U87MG xenograft tumor models. Good tumor targeting was observed in T1-weighted MRI images; whereby the unbound nanoparticles were efficiently excreted through renal clearance, avoiding long-term toxicity to the host.
Co-reporter:Hongmin Chen, Geoffrey D. Wang, Yen-Jun Chuang, Zipeng Zhen, Xiaoyuan Chen, Paul Biddinger, Zhonglin Hao, Feng Liu, Baozhong Shen, Zhengwei Pan, and Jin Xie
Nano Letters 2015 Volume 15(Issue 4) pp:2249-2256
Publication Date(Web):March 10, 2015
DOI:10.1021/nl504044p
Photodynamic therapy is a promising treatment method, but its applications are limited by the shallow penetration of visible light. Here, we report a novel X-ray inducible photodynamic therapy (X-PDT) approach that allows PDT to be regulated by X-rays. Upon X-ray irradiation, the integrated nanosystem, comprised of a core of a nanoscintillator and a mesoporous silica coating loaded with photosensitizers, converts X-ray photons to visible photons to activate the photosensitizers and cause efficient tumor shrinkage.
Co-reporter:Zipeng Zhen, Wei Tang, Weizhong Zhang and Jin Xie
Nanoscale 2015 vol. 7(Issue 23) pp:10330-10333
Publication Date(Web):11 May 2015
DOI:10.1039/C5NR01833A
We coupled folic acid as a tumour targeting ligand to the surface of ferritins and loaded them with ZnF16Pc. The resulting nanoconjugates can efficiently hone in on 4T1 tumours in vivo, and, with photoirradiation, leading to suppressed tumour growth and tumour metastasis.
Co-reporter:Hongmin Chen;Geoffrey D. Wang;Wei Tang;Trever Todd;Zipeng Zhen;Chu Tsang;Khan Hekmatyar;Taku Cowger;Richard B. Hubbard;Weizhong Zhang;John Stickney;Baozhong Shen
Advanced Materials 2014 Volume 26( Issue 39) pp:6761-6766
Publication Date(Web):
DOI:10.1002/adma.201402964
Co-reporter:Zipeng Zhen, Wei Tang, Yen-Jun Chuang, Trever Todd, Weizhong Zhang, Xin Lin, Gang Niu, Gang Liu, Lianchun Wang, Zhengwei Pan, Xiaoyuan Chen, and Jin Xie
ACS Nano 2014 Volume 8(Issue 6) pp:6004
Publication Date(Web):May 7, 2014
DOI:10.1021/nn501134q
Delivery of nanoparticle drugs to tumors relies heavily on the enhanced permeability and retention (EPR) effect. While many consider the effect to be equally effective on all tumors, it varies drastically among the tumors’ origins, stages, and organs, owing much to differences in vessel leakiness. Suboptimal EPR effect represents a major problem in the translation of nanomedicine to the clinic. In the present study, we introduce a photodynamic therapy (PDT)-based EPR enhancement technology. The method uses RGD-modified ferritin (RFRT) as “smart” carriers that site-specifically deliver 1O2 to the tumor endothelium. The photodynamic stimulus can cause permeabilized tumor vessels that facilitate extravasation of nanoparticles at the sites. The method has proven to be safe, selective, and effective. Increased tumor uptake was observed with a wide range of nanoparticles by as much as 20.08-fold. It is expected that the methodology can find wide applications in the area of nanomedicine.Keywords: drug delivery; EPR; ferritin; integrin αvβ3; nanoparticles; photodynamic therapy
Co-reporter:Hongmin Chen, Zipeng Zhen, Trever Todd, Paul K. Chu, Jin Xie
Materials Science and Engineering: R: Reports 2013 Volume 74(Issue 3) pp:35-69
Publication Date(Web):March 2013
DOI:10.1016/j.mser.2013.03.001
Despite the progress in developing new therapeutic modalities, cancer remains one of the leading diseases causing human mortality. This is mainly attributed to the inability to diagnose tumors in their early stage. By the time the tumor is confirmed, the cancer may have already metastasized, thereby making therapies challenging or even impossible. It is therefore crucial to develop new or to improve existing diagnostic tools to enable diagnosis of cancer in its early or even pre-syndrome stage. The emergence of nanotechnology has provided such a possibility. Unique physical and physiochemical properties allow nanoparticles to be utilized as tags with excellent sensitivity. When coupled with the appropriate targeting molecules, nanoparticle-based probes can interact with a biological system and sense biological changes on the molecular level with unprecedented accuracy. In the past several years, much progress has been made in applying nanotechnology to clinical imaging and diagnostics, and interdisciplinary efforts have made an impact on clinical cancer management. This article aims to review the progress in this exciting area with emphases on the preparation and engineering techniques that have been developed to assemble “smart” nanoprobes.
Co-reporter:Zipeng Zhen, Wei Tang, Hongmin Chen, Xin Lin, Trever Todd, Geoffrey Wang, Taku Cowger, Xiaoyuan Chen, and Jin Xie
ACS Nano 2013 Volume 7(Issue 6) pp:4830
Publication Date(Web):May 29, 2013
DOI:10.1021/nn305791q
Ferritin (FRT) is a major iron storage protein found in humans and most living organisms. Each ferritin is composed of 24 subunits, which self-assemble to form a cage-like nanostructure. FRT nanocages can be genetically modified to present a peptide sequence on the surface. Recently, we demonstrated that Cys-Asp-Cys-Arg-Gly-Asp-Cys-Phe-Cys (RGD4C)-modified ferritin can efficiently home to tumors through RGD–integrin αvβ3 interaction. Though promising, studies on evaluating surface modified ferritin nanocages as drug delivery vehicles have seldom been reported. Herein, we showed that after being precomplexed with Cu(II), doxorubicin can be loaded onto RGD modified apoferritin nanocages with high efficiency (up to 73.49 wt %). When studied on U87MG subcutaneous tumor models, these doxorubicin-loaded ferritin nanocages showed a longer circulation half-life, higher tumor uptake, better tumor growth inhibition, and less cardiotoxicity than free doxorubicin. Such a technology might be extended to load a broad range of therapeutics and holds great potential in clinical translation.Keywords: doxorubicin; drug delivery; ferritin; integrin αvβ3; nanocarrier
Co-reporter:Zipeng Zhen, Wei Tang, Cunlan Guo, Hongmin Chen, Xin Lin, Gang Liu, Baowei Fei, Xiaoyuan Chen, Binqian Xu, and Jin Xie
ACS Nano 2013 Volume 7(Issue 8) pp:6988
Publication Date(Web):July 6, 2013
DOI:10.1021/nn402199g
Photodynamic therapy is an emerging treatment modality that is under intensive preclinical and clinical investigations for many types of disease including cancer. Despite the promise, there is a lack of a reliable drug delivery vehicle that can transport photosensitizers (PSs) to tumors in a site-specific manner. Previous efforts have been focused on polymer- or liposome-based nanocarriers, which are usually associated with a suboptimal PS loading rate and a large particle size. We report herein that a RGD4C-modified ferritin (RFRT), a protein-based nanoparticle, can serve as a safe and efficient PS vehicle. Zinc hexadecafluorophthalocyanine (ZnF16Pc), a potent PS with a high 1O2 quantum yield but poor water solubility, can be encapsulated into RFRTs with a loading rate as high as ∼60 wt % (i.e., 1.5 mg of ZnF16Pc can be loaded on 1 mg of RFRTs), which far exceeds those reported previously. Despite the high loading, the ZnF16Pc-loaded RFRTs (P-RFRTs) show an overall particle size of 18.6 ± 2.6 nm, which is significantly smaller than other PS–nanocarrier conjugates. When tested on U87MG subcutaneous tumor models, P-RFRTs showed a high tumor accumulation rate (tumor-to-normal tissue ratio of 26.82 ± 4.07 at 24 h), a good tumor inhibition rate (83.64% on day 12), as well as minimal toxicity to the skin and other major organs. This technology can be extended to deliver other metal-containing PSs and holds great clinical translation potential.Keywords: ferritin; nanoparticle; photodynamic therapy; photosensitizer; targeted delivery