Peptide Mediated In Vivo Tumor Targeting of Nanoparticles through Optimization in Single and Multilayer In Vitro Cell Models.

Published on Mar 20, 2018in Cancers6.126
· DOI :10.3390/CANCERS10030084
Celina Yang8
Estimated H-index: 8
(RyeU: Ryerson University),
Kyle Bromma7
Estimated H-index: 7
(UVic: University of Victoria),
Devika B. Chithrani17
Estimated H-index: 17
(RyeU: Ryerson University)
Optimizing the interface between nanoparticles (NPs) and the biological environment at various levels should be considered for improving delivery of NPs to the target tumor area. For NPs to be successfully delivered to cancer cells, NPs needs to be functionalized for circulation through the blood vessels. In this study, accumulation of Polyethylene Glycol (PEG) functionalized gold nanoparticles (GNPs) was first tested using in vitro monolayer cells and multilayer cell models prior to in vivo models. A diameter of 10 nm sized GNP was selected for this study for sufficient penetration through tumor tissue. The surfaces of the GNPs were modified with PEG molecules, to improve circulation time by reducing non-specific uptake by the reticuloendothelial system (RES) in animal models, and with a peptide containing integrin binding domain, RGD (arginyl-glycyl-aspartic acid), to improve internalization at the cellular level. A 10–12% accumulation of the injected GNP dose within the tumor was observed in vivo and the GNPs remained within the tumor tissue up to 72 h. This study suggests an in vitro platform for optimizing the accumulation of NP complexes in cells and tissue structures before testing them in animal models. Higher accumulation within the tumor in vivo upon surface modification is a promising outcome for future applications where GNPs can be used for drug delivery and radiation therapy.
📖 Papers frequently viewed together
97 Citations
20153.12RSC Advances
5 Authors (C. Cruje, ..., B. D. Chithrani)
17 Citations
416 Citations
#1Tianjiao Ji (CAS: Chinese Academy of Sciences)H-Index: 23
#2Jiayan Lang (CAS: Chinese Academy of Sciences)H-Index: 12
Last. Guangjun Nie (CAS: Chinese Academy of Sciences)H-Index: 57
view all 13 authors...
During pancreatic tumor development, pancreatic stellate cells (PSCs) proliferate exuberantly to secrete extracellular matrix (ECM) in the tumor stroma, which presents major barriers for drug delivery and penetration in tumor tissue. Thus, down-regulating ECM levels via regulation of the PSCs may allow enhanced penetration of therapeutic drugs and thereby enhancing their therapeutic efficacy. To regulate the PSCs, a matrix metalloproteinase-2 (MMP-2) responsive peptide-hybrid liposome (MRPL) was...
63 CitationsSource
#1Matthew Ware (BCM: Baylor College of Medicine)H-Index: 10
#2Louis T. Curtis (University of Louisville)H-Index: 10
Last. Hermann B. Frieboes (University of Louisville)H-Index: 30
view all 8 authors...
Although chemotherapy combined with radiofrequency exposure has shown promise in cancer treatment by coupling drug cytotoxicity with thermal ablation or thermally-induced cytotoxicity, limited access of the drug to tumor loci in hypo-vascularized lesions has hampered clinical application. We recently showed that high-intensity short-wave capacitively coupled radiofrequency (RF) electric-fields may reach inaccessible targets in vivo. This non-invasive RF combined with gemcitabine (Gem) chemothera...
7 CitationsSource
#1Mengmeng Liu (CAS: Chinese Academy of Sciences)H-Index: 20
#1Mengmeng Liu (CAS: Chinese Academy of Sciences)H-Index: 4
Last. Chunhai Fan (CAS: Chinese Academy of Sciences)H-Index: 116
view all 14 authors...
The interaction of nanoparticles intracellularly has been investigated widely but the mechanisms of such interactions are not fully understood. Here, the authors utilize a semi-quantitative technique to assess the intracellular transportation and clustering potential of nanoparticles in real-time.
75 CitationsSource
#1Matthew Ware (BCM: Baylor College of Medicine)H-Index: 10
#2Vazrik Keshishian (BCM: Baylor College of Medicine)H-Index: 4
Last. Steven A. Curley (BCM: Baylor College of Medicine)H-Index: 11
view all 16 authors...
Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent desmoplastic/stromal reaction, which contributes to the poor clinical outcome of this disease. Therefore, greater understanding of the stroma development and tumor-stroma interactions is highly required. Pancreatic stellate cells (PSC) are myofibroblast-like cells located in exocrine areas of the pancreas, which as a result of inflammation produced by PDAC migrate and accumulate in the tumor mass, secreting extracel...
59 CitationsSource
#1Agnieszka Zuber (University of Adelaide)H-Index: 4
#2Malcolm S. Purdey (University of Adelaide)H-Index: 8
Last. Heike Ebendorff-Heidepriem (University of Adelaide)H-Index: 48
view all 9 authors...
Abstract Growing world demand for gold and decreasing discovery rates of ore deposits necessitates new techniques for gold exploration. Current techniques for the detection of ppb level of gold, such as inductively coupled plasma mass spectrometry (ICP-MS) are not field-deployable. By contrast, current portable device such as X-ray fluorescence (XRF) based sensors are not sufficiently sensitive. Thus, there is growing interest in developing a new, easy-to-use and fast method for detection of low...
80 CitationsSource
#1Shrey Sindhwani (U of T: University of Toronto)H-Index: 12
#2Abdullah Muhammad Syed (U of T: University of Toronto)H-Index: 12
Last. Warren C. W. Chan (U of T: University of Toronto)H-Index: 78
view all 7 authors...
The role of tissue architecture in mediating nanoparticle transport, targeting, and biological effects is unknown due to the lack of tools for imaging nanomaterials in whole organs. Here, we developed a rapid optical mapping technique to image nanomaterials in intact organs ex vivo and in three-dimensions (3D). We engineered a high-throughput electrophoretic flow device to simultaneously transform up to 48 tissues into optically transparent structures, allowing subcellular imaging of nanomateria...
39 CitationsSource
#1Stefan Wilhelm (U of T: University of Toronto)H-Index: 19
#2Anthony J. Tavares (U of T: University of Toronto)H-Index: 15
Last. Warren C. W. Chan (U of T: University of Toronto)H-Index: 78
view all 7 authors...
This Perspective explores and explains the fundamental dogma of nanoparticle delivery to tumours and answers two central questions: ‘how many nanoparticles accumulate in a tumour?’ and ‘how does this number affect the clinical translation of nanomedicines?’
1,609 CitationsSource
#1Rebecca L. Siegel (ACS: American Cancer Society)H-Index: 67
#2Kimberly D. Miller (ACS: American Cancer Society)H-Index: 28
Last. Ahmedin Jemal (ACS: American Cancer Society)H-Index: 140
view all 3 authors...
Abstract Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data were collected by the National Cancer Institute (Surveillance, Epidemiology, and End Results [SEER] Program), the Centers for Disease Control and Prevention (National Program of Cancer Registries), and the North American Association of Central Can...
10.8k CitationsSource
#1C. Cruje (RyeU: Ryerson University)H-Index: 1
#2Celina Yang (RyeU: Ryerson University)H-Index: 8
Last. B. D. Chithrani (RyeU: Ryerson University)H-Index: 2
view all 5 authors...
Nanoscale gold particles are being used as a radiation dose enhancer in cancer research. The purpose of this study was to optimize the uptake of polyethylene glycol (PEG) functionalized gold nanoparticles (GNPs) for an enhanced therapeutic effect during radiation therapy. PEG is widely used in providing NPs with stealth properties, thus prolonging blood circulation times. However, PEG minimizes PEG-GNP interaction with cell surface ligands resulting in significantly lower in vitro cellular uptak...
17 CitationsSource
#1Darren Yohan (RyeU: Ryerson University)H-Index: 8
#2Charmainne Cruje (RyeU: Ryerson University)H-Index: 4
Last. Devika B. Chithrani (RyeU: Ryerson University)H-Index: 17
view all 4 authors...
Multicellular layers (MCLs) have previously been used to determine the pharmacokinetics of a variety of different cancer drugs including paclitaxel, doxorubicin, methotrexate, and 5-fluorouracil across a number of cell lines. It is not known how nanoparticles (NPs) navigate through the tumor microenvironment once they leave the tumor blood vessel. In this study, we used the MCL model to study the uptake and penetration dynamics of NPs. Gold nanoparticles (GNPs) were used as a model system to map...
13 CitationsSource
Cited By15
#1Cynthia L. Schreiber (ND: University of Notre Dame)H-Index: 7
#2Canjia Zhai (ND: University of Notre Dame)H-Index: 4
Last. Bradley D. Smith (ND: University of Notre Dame)H-Index: 72
view all 3 authors...
Squaraine figure-eight (SF8) molecules are a new class of deep-red fluorescent probes that are well suited for fluorescence cell microscopy due to their very high fluorescence brightness and excellent stability. Three homologous SF8 probes, with peptidyl loops that differ by very minor changes in the peptide sequence, were synthesized and assessed for probe uptake by cancer cells. One of probes included the RGD motif that is recognized by many classes of integrin receptors that reside on the sur...
About half of cancer patients (50%) receive radiotherapy (RT) for the treatment of local tumors. However, one of the main obstacles in RT is the close proximity of adjacent organs at risk, resulting in treatment doses being limited by significant tissue toxicity, hence preventing the necessary dose escalation that would guarantee local control. Effective local cancer therapy is needed to avoid progression of tumors and to decrease the development of systemic metastases which may further increase...
#1Ruchika Goyal (IITG: Indian Institute of Technology Guwahati)H-Index: 3
#2Gaurav Jerath (IITG: Indian Institute of Technology Guwahati)H-Index: 5
Last. Vibin Ramakrishnan (IITG: Indian Institute of Technology Guwahati)H-Index: 11
view all 10 authors...
Abstract Poly-peptide molecules have shown promising applications in drug delivery and tumor targeting. A series of tumor homing peptides were designed by exhaustively sampling low energy geometrical basins of amino acids at specific sites of a peptide molecule to induce a conformational lock. This peptide library was pruned to a limited set of eight molecules, employing electrostatic interactions, docking, and molecular dynamics simulations. These designed and optimized peptides were synthesize...
#2Xinyu WangH-Index: 1
Last. Zhongcai Fan (MOE: Chinese Ministry of Education)H-Index: 3
view all 5 authors...
With the advent of nanofabrication techniques, plasmonic nanoparticles (PNPs) have been widely applied in various research fields ranging from photocatalysis to chemical and bio-sensing. PNPs efficiently convert chemical or physical stimuli in their local environment into optical signals. PNPs also have excellent properties, including good biocompatibility, large surfaces for the attachment of biomolecules, tunable optical properties, strong and stable scattering light, and good conductivity. Th...
#1Zimu Li (SYSU: Sun Yat-sen University)H-Index: 4
#2Xiaoting Shan (SYSU: Sun Yat-sen University)H-Index: 1
Last. Lin Mei (SYSU: Sun Yat-sen University)H-Index: 19
view all 7 authors...
The impermeable barrier of solid tumors due to the complexity of their components limits the treatment effect of nanomedicine and hinders its clinical translation. Several methods are available to increase the penetrability of nanomedicine, yet they are too complex to be effective, operational, or practical. Surface modification employs the characteristics of direct contact between multiphase surfaces to achieve the most direct and efficient penetration of solid tumors. Furthermore, their simple...
4 CitationsSource
According to the global cancer observatory (GLOBOCAN), there are approximately 18 million new cancer cases per year worldwide. Cancer therapies are largely limited to surgery, radiotherapy, and chemotherapy. In radiotherapy and chemotherapy, the maximum tolerated dose is presently being used to treat cancer patients. The integrated development of innovative nanoparticle (NP) based approaches will be a key to address one of the main issues in both radiotherapy and chemotherapy: normal tissue toxi...
5 CitationsSource
#1Kyle Bromma (UVic: University of Victoria)H-Index: 7
#2Aaron Bannister (UVic: University of Victoria)H-Index: 3
Last. Devika B. Chithrani (UVic: University of Victoria)H-Index: 17
view all 5 authors...
Successful integration of nanotechnology into the current paradigm of cancer therapy requires proper understanding of the interface between nanoparticles (NPs) and cancer cells, as well as other key components within the tumor microenvironment (TME), such as normal fibroblasts (FBs) and cancer-associated FBs (CAFs). So far, much focus has been on cancer cells, but FBs and CAFs also play a critical role: FBs suppress the tumor growth while CAFs promote it. It is not yet known how NPs interact wit...
2 CitationsSource
#1Kyle Bromma (UVic: University of Victoria)H-Index: 7
#2Leah Cicon (UVic: University of Victoria)H-Index: 3
Last. Devika B. ChithraniH-Index: 17
view all 4 authors...
One of the major issues in cancer radiotherapy (RT) is normal tissue toxicity. Introduction of radiosensitizers like gold nanoparticles (GNPs) into cancer cells to enhance the local RT dose has been tested successfully. However, it is not known how GNPs interact with other stromal cells such as normal fibroblasts (FBs) and cancer associated fibroblasts (CAFs) within the tumour microenvironment. It is known that FBs turn into CAFs to promote tumour growth. Hence, we used FBs and CAFs along with H...
5 CitationsSource
#1Aaron Bannister (UVic: University of Victoria)H-Index: 3
#2Dushanthi Dissanayake (UVic: University of Victoria)H-Index: 1
Last. Devika B. Chithrani (UVic: University of Victoria)H-Index: 17
view all 6 authors...
Nanoparticles (NPs) have shown promise in both radiotherapy and chemotherapy. NPs are mainly transported along cellular microtubules (MTs). Docetaxel (DTX) is a commonly used chemotherapeutic drug that can manipulate the cellular MT network to maximize its clinical benefit. However, the effect of DTX on NP behaviour has not yet been fully elucidated. We used gold NPs of diameters 15 and 50 nm at a concentration of 0.2 nM to investigate the size dependence of NP behaviour. Meanwhile, DTX concentr...
1 CitationsSource
#1Jan Schuemann (Harvard University)H-Index: 23
#2Alexander F. Bagley (University of Texas MD Anderson Cancer Center)H-Index: 4
Last. Sunil Krishnan (Mayo Clinic)H-Index: 79
view all 42 authors...
This roadmap outlines the potential roles of metallic nanoparticles (MNPs) in the field of radiation therapy. MNPs made up of a wide range of materials (from Titanium, Z=22, to Bismuth, Z=83) and a similarly wide spectrum of potential clinical applications, including diagnostic, therapeutic (radiation dose enhancers, hyperthermia inducers, drug delivery vehicles, vaccine adjuvants, photosensitizers, enhancers of immunotherapy) and theranostic (combining both diagnostic and therapeutic), are bein...
14 CitationsSource