Enhanced Permeability Retention Research Articles

Engineered nanomaterials enhance drug delivery strategies for the treatment of osteosarcoma.

Osteosarcoma (OS) is the most common malignant bone tumor in adolescents, and the clinical treatment of OS mainly includes surgery, radiotherapy, and chemotherapy. However, the side effects of chemotherapy drugs are an issue that clinicians cannot ignore. Nanomedicine and drug delivery technologies play an important role in modern medicine. The development of nanomedicine has ushered in a new turning point in tumor treatment. With the emergence and development of nanoparticles, nanoparticle energy surfaces can be designed with different targeting effects. Not only that, nanoparticles have unique advantages in drug delivery. Nanoparticle delivery drugs can not only reduce the toxic side effects of chemotherapy drugs, but due to the enhanced permeability retention (EPR) properties of tumor cells, nanoparticles can survive longer in the tumor microenvironment and continuously release carriers to tumor cells. Preclinical studies have confirmed that nanoparticles can effectively delay tumor growth and improve the survival rate of OS patients. In this manuscript, we present the role of nanoparticles with different functions in the treatment of OS and look forward to the future treatment of improved nanoparticles in OS.

Phosphorus core-shell tecto dendrimers for enhanced tumor imaging: the rigidity of the backbone matters.

Nanoplatforms with amplified passive tumor targeting and enhanced protein resistance can evade unnecessary uptake by the reticuloendothelial system and achieve high tumor retention for accurate tumor theranostics. To achieve this goal, we here constructed phosphorus core-shell tecto dendrimers (CSTDs) with a rigid aromatic backbone core as a nanoplatform for enhanced fluorescence and single-photon emission computed tomography (SPECT) dual-mode imaging of tumors. In this study, the phosphorus P-G2.5/G3 CSTDs (G denotes generation) were partially conjugated with tetraazacyclododecane tetraacetic acid (DOTA), cyanine5.5 (Cy5.5) and 1,3-propane sulfonate (1,3-PS) and then labeled with 99mTc. The formed P-G2.5/G3-DOTA-Cy5.5-PS CSTDs possess good monodispersity with a particle size of 10.1 nm and desired protein resistance and cytocompatibility. Strikingly, compared to the counterpart material G3/G3-DOTA-Cy5.5-PS with both the core and shell components being soft poly(amidoamine) dendrimers, the developed P-G2.5/G3-DOTA-Cy5.5-PS complexes allow for more efficient cellular uptake and more significant penetration in 3-dimensional tumor spheroids in vitro, as well as more significant tumor retention and accumulation for enhanced dual-mode fluorescence and SPECT (after labelling with 99mTc) tumor imaging in vivo. Our studies suggest that the rigidity of the core for the constructed CSTDs matters in the amplification of the tumor enhanced permeability retention (EPR) effect for improved cancer nanomedicine development.

Inhibitory effects and gene expression analysis of chemotherapeutic photodynamic therapy by using a liposomally formulated indocyanine green derivative

BackgroundPhotodynamic therapy (PDT) utilizes the enhanced permeability retention effect of photosensitizers and is less invasive and more selective than traditional chemotherapy. We constructed a chemotherapeutic PDT (chemo-PDT) nanoscale drug delivery system using a liposomally formulated indocyanine green derivative (ICG-Lipo) that encapsulated carboplatin and docetaxel (ICG-Lipo-C&D). MethodsThe antitumor effect of chemo-PDT mediated by ICG-Lipo-C&D was evaluated in a murine colon 26 CDF1 mouse model. Gene expression in tumor tissues was analyzed by RNA sequencing. ResultsChemo-PDT using ICG-Lipo-C&D demonstrated an even stronger PDT-enhancing effect than did ICG-Lipo due to the synergistic effect of carboplatin and docetaxel. In addition, gene expression analysis showed that PDT with ICG-Lipo-C&D increased the expression of immune-related genes and decreased the expression of cytoskeleton-related genes. ConclusionsChemo-PDT using ICG-Lipo as a photosensitizer as well as a drug delivery system with an enhanced permeability retention effect may be a promising cancer therapy.

Tumor-targeted hyaluronic acid-based oxidative stress nanoamplifier with ROS generation and GSH depletion for antitumor therapy

Tumor cells with innate oxidative stress are more susceptible to exogenous ROS-mediated oxidative damage than normal cells. However, the generated ROS could be scavenged by the overexpressed GSH in cancer cells, thus causing greatly restricted efficiency of ROS-mediated antitumor therapy. Herein, using cinnamaldehyde (CA) as a ROS generator while β-phenethyl isothiocyanate (PEITC) as a GSH scavenger, we designed a tumor-targeted oxidative stress nanoamplifier to elevate intracellular ROS level and synchronously suppress antioxidant systems, for thorough redox imbalance and effective tumor cells killing. First, an amphiphilic acid-sensitive cinnamaldehyde-modified hyaluronic acid conjugates (HA-CA) were synthesized, which could self-assemble into nano-assembly in aqueous media via strong hydrophobic interaction and π-π stacking. Then, aromatic PEITC was appropriately encapsulated into HA-CA nano-assembly to obtain HA-CA/PEITC nanoparticles. Through enhanced permeability retention (EPR) effect and specific CD44 receptor-mediated endocytosis, HA-CA/PEITC nanoparticles could accumulate in tumor tissues and successfully release CA and PEITC under acidic lysosomal environment. Both in vitro and in vivo results showed that the nanoparticles could efficiently boost oxidative stress of tumor cells via generating ROS and depleting GSH, and finally achieve superior antitumor efficacy. This nanoamplifier with good biosafety provides a potential strategy to augment ROS generation and suppress GSH for enhanced oxidation therapy.

NIR Activated Upper Critical Solution Temperature Polymeric Micelles for Trimodal Combinational Cancer Therapy.

The balance between drug efficiency and its side effects on normal tissues is still a challenging problem to be solved in current cancer therapies. Among different strategies, cancer therapeutic methods based on nanomedicine delivery systems have received extensive attention due to their unique advantages such as improved circulation and reduced toxicity of drugs in the body. Herein, we constructed dual-responsive polymeric micelles DOX&ALS@MFM based on an upper critical solution temperature (UCST) polymer to simultaneously combine chemotherapy, photothermal therapy (PTT), and photodynamic therapy (PDT). Amphiphilic block copolymer P(AAm-co-AN)-b-PEI-ss-PEG-FA with a critical point of 42 °C was able to self-assemble into polymeric micelles under physiological conditions, which further encapsulated anticancer drug doxorubicin (DOX) and photosensitizer ALS to obtain drug-loaded micelles DOX&ALS@MFM. Micelles aggregated at tumor sites due to folate targeting and an enhanced permeability retention (EPR) effect. After that, the high intracellular concentration of glutathione (GSH) and near-infrared (NIR) light prompted disassembly of the polymer to release DOX and ALS. ALS not only plays a role in PTT but also produces singlet oxygen, therefore killing tumor cells by PDT. Both in vitro and in vivo studies demonstrated the photothermal conversion and reactive oxygen species generation ability of DOX&ALS@MFM micelles, at the same time as the excellent inhibitory effect on tumor growth with NIR light irradiation. Thus, our research substantiated a new strategy for the biomedical application of UCST polymers in the cited triple modal tumor therapy.

Synthesis of self-assembled hyaluronan based nanoparticles and their applications in targeted imaging and therapy

Hyaluronan (HA) is a polysaccharide consisting of repeating disaccharides of N-acetyl-d-glucosamine and d-glucuronic acid. There are increasing interests in utilizing self-assembled HA nanoparticles (HA-NPs) for targeted imaging and therapy. The principal endogenous receptor of HA, cluster of differentiation 44 (CD44), is overexpressed on many types of tumor cells as well as inflammatory cells in human bodies. Active targeting from HA-CD44 mediated interaction and passive targeting due to the enhanced permeability retention (EPR) effect could lead to selective accumulation of HA-NPs at targeted disease sites. This review focuses on the synthesis strategies of self-assembled HA-NPs, as well as their applications in therapy and biomedical imaging.

Reappraisal of anticancer nanomedicine design criteria in three types of preclinical cancer models for better clinical translation

Anticancer nanomedicines are designed to improve anticancer efficacy by increasing drug accumulation in tumors through enhanced permeability retention (EPR) effect, and to reduce toxicity by decreasing drug accumulation in normal organs through long systemic circulation. However, the inconsistent efficacy/safety of nanomedicines in cancer patients versus preclinical cancer models have provoked debate for nanomedicine design criteria. In this study, we investigate nanomedicine design criteria in three types of preclinical cancer models using five clinically used nanomedicines, which identifies the factors for better clinical translations of their observed clinical efficacy/safety compared to free drug or clinical micelle formulation. When those nanomedicines were compared with drug solution or clinical micelle formulation in breast tumors, long and short-circulating nanomedicines did not enhance tumor accumulation by EPR effect in transgenic spontaneous breast cancer model regardless of their size or composition, although they improved tumor accumulations in subcutaneous and orthotopic breast cancer models. However, when tumors were compared to normal breast tissue, nanomedicines, drug solution and clinical micelle formulation showed enhanced tumor accumulation regardless of the breast cancer models. In addition, long-circulating nanomedicines did not further increase tumor accumulation in transgenic mouse spontaneous breast cancer nor universally decrease drug accumulations in normal organs; they decreased or increased accumulation in different organs, potentially changing the clinical efficacy/safety. In contrast, short-circulating nanomedicines decreased blood concentration and altered drug distribution in normal organs, which are correlated with their clinical efficacy/safety. A reappraisal of current nanomedicine design criteria is needed to ensure consistent clinical translation for improvement of their clinical efficacy/safety in cancer patients.

Doxorubicin (DOX) Gadolinium-Gold-Complex: A New Way to Tune Hybrid Nanorods as Theranostic Agent.

IntroductionIn this paper, we have designed and formulated, a novel synthesis of doxorubicin (DOX) loaded bimetallic gold nanorods in which gold salt (HAuCl4) is chelated with anthracycline (DOX), diacid polyethylene-glycol (PEG-COOH) and gadolinium salt (GdCl3 * 6 H2O) to form DOX IN-Gd-AuNRs compared with DOX ON-Gd-AuNRs in which the drug was grafted onto the bimetallic pegylated nanoparticle surface by electrostatic adsorption.Material and MethodThe physical and chemical evaluation was performed by spectroscopic analytical techniques (Raman spectroscopy, UV-Visible and transmission electron microscopy (TEM)). Magnetic features at 7T were also measured. Photothermal abilities were assessed. Cytotoxicity studies on MIA PaCa-2, human pancreatic carcinoma and TIB-75 hepatocytes cell lines were carried out to evaluate their biocompatibility and showed a 320 fold higher efficiency for DOX after encapsulation.ResultsExhaustive physicochemical characterization studies were conducted showing a mid size of 20 to 40 nm diameters obtained with low polydispersity, efficient synthesis using seed mediated synthesis with chelation reaction with high scale-up, long duration stability, specific doxorubicin release with acidic pH, strong photothermal abilities at 808 nm in the NIR transparency window, strong magnetic r1 relaxivities for positive MRI, well adapted for image guided therapy and therapeutical purpose in biological tissues.ConclusionIn this paper, we have developed a novel theranostic nanoparticle composed of gadolinium complexes to gold ions, with a PEG biopolymer matrix conjugated with antitumoral doxorubicin, providing multifunctional therapeutic features. Particularly, these nano conjugates enhanced the cytotoxicity toward tumoral MIAPaCa-2 cells by a factor of 320 compared to doxorubicin alone. Moreover, MRI T1 features at 7T enables interesting positive contrast for bioimaging and their adapted size for potential passive targeting to tumors by Enhanced Permeability Retention. Given these encouraging antitumoral and imaging properties, this bimetallic theranostic nanomaterial system represents a veritable promise as a therapeutic entity in the field of medicinal applications.

Multistage-responsive clustered nanosystem to improve tumor accumulation and penetration for photothermal/enhanced radiation synergistic therapy

Developing new strategies to overcome biological barriers and achieve efficient delivery of therapeutic nanoparticles (NPs) is the key to achieve positive therapeutic outcomes in nanomedicine. Herein, a multistage-responsive clustered nanosystem is designed to systematically resolve the multiple tumor biological barriers conflict between the enhanced permeability retention (EPR) effect and spatially uniform penetration of the nanoparticles. The nanosystem with desirable diameter (initial size of ~50 nm), which is favorable for long blood circulation and high propensity of extravasation through tumor vascular interstices, can accumulate effectively around the tumor tissue through the EPR effect. Then, these pH-responsive nanoparticles are conglomerated to form large-sized aggregates (~1000 nm) in the tumor under the acidic microenvironment, and demonstrated great tumor retention. Subsequently, the photothermal treatment disperses the aggregates to be ultrasmall gold nanoclusters (~5 nm), thereby improving their tumor penetration ability, and enhancing the radiotherapeutic effect by radiosensitizer. In 4T1 tumor model, this nanosystem shows great tumor accumulation and penetration, and the tumor growth and the lung/liver metastasis in particle/PTT/RT treated mice is significantly inhibited. As a photoacoustic/fluorescence imaging agent and PT/RT synergistic agent, this pH-/laser-triggered size multistage-responsive nanosystem displayes both great tumor accumulation and penetration abilities, and shows excellent potential in tumor therapy.

The enhanced permeability and retention effect based nanomedicine at the site of injury

The enhanced permeability retention (EPR) effect based nanomedicine has been widely used for tumor targeting during the past decades. Here we unexpectedly observed the similar “EPR effect” at the site of injury. We found that the temporary dilated and leaky blood vessels caused by the potent vasodilator histamine in response to injury allowed the injected nanoparticles to pass through the vasculature and reached the injured tissue. Our finding shows the potential underline mechanism of “EPR effect” at the injured site. By loading with antibiotics, we further demonstrated a new strategy for prevention of infection at the site of injury.

Antibody Targeted PET Imaging of 64Cu-DOTA-Anti-CEA PEGylated Lipid Nanodiscs in CEA Positive Tumors.

Lipid nanodiscs (LNDs), comprising a phospholipid bilayer encircled by two molecules of a recombinant membrane scaffold protein, can be targeted to tumors with covalently attached antibodies (Abs) or their fragments. Antibody attachment to click chemistry based PEGylated lipids on LNDs including DOTA allowed PET imaging with the positron emitter 64Cu. Carcinoembryonic antigen (CEA) positive tumors in CEA transgenic mice were chosen as a tumor target. Fab' fragments, that otherwise are rapidly cleared by the kidney due to their small size, were retained in circulation when conjugated to LNDs. Untargeted PET imaging of 64Cu-DOTA-LNDs revealed low tumor uptake (4-5% ID/g) in the range expected for the enhanced permeability retention (EPR) effect with high liver uptake (17-21% ID/g) indicating gut clearance. Fab' targeted LNDs showed little improvement over untargeted LNDs, but intact IgG targeted LNDs gave high tumor uptake (40% ID/g) with low liver (8% ID/g), demonstrating that tumor targeting with antibody conjugated LNDs is feasible.

Synthesis and Relaxometric Characterization of New Poly[N,N-bis(3-aminopropyl)glycine] (PAPGly) Dendrons Gd-Based Contrast Agents and Their in Vivo Study by Using the Dynamic Contrast-Enhanced MRI Technique at Low Field (1 T).

The synthesis of poly[N,N-bis(3-aminopropyl)glycine] (PAPGly) dendrons Gd-based contrast agents (GdCAs) via an orthogonal protection of the different functional groups and an activation/coupling strategy wherein a specific number of synthetic steps add a generation to the existing dendron has been described. The aim of this protocol is to build up two different generations of dendrons (G-0 or dendron's core, and G-1) with peripheral NH2 groups to conjugate a 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A) derivative and afterwards to chelate with Gd3+ paramagnetic ions. These complexes, which have a well-defined molecular weight, are of relevance to MRI as an attempt to gain higher 1 H relaxivity by slowing down the rotation of molecule compared to monomeric Gd(III) complexes used as contrast agents and to increase the number of paramagnetic centers present in one molecular structure. From the study of their water 1 H longitudinal relaxation rate at different magnetic fields (NMRD, Nuclear Magnetic Relaxation Dispersion) and by evaluating the variable temperature 17 O-NMR data we determined the parameters characterizing the water exchange rate and the rotational correlation time of each complex, both affecting 1 H relaxivity. Furthermore, these two novel PAPGly GdCAs were objects of i) an in vivo study to determine their biodistributions in healthy C57 mice at several time points, and ii) the Dynamic Contrast-Enhanced MRI (DCE-MRI) approach to assess their contrast efficiency measured in the tumor region of C57BL/6 mice transplanted subcutaneously with B16-F10 melanoma cells. The aim of the comparison of these two dendrons GdCAs, having different molecular weights (MW), is to understand how MW and relaxivity may influence the contrast enhancement capabilities in vivo at low magnetic field (1 T). Significant contrast enhancement was observed in several organs (vessel, spleen and liver), already at 5 min post-injection, for the investigated CAs. Moreover, these CAs induced a marked contrast enhancement in the tumor region, thanks to the enhanced permeability retention effect of those macromolecular structures.

A phase 0 study of the pharmacokinetics, biodistribution, and dosimetry of 188Re-liposome in patients with metastatic tumors

BackgroundLiposomes are drug nano-carriers that are capable of targeting therapeutics to tumor sites because of enhanced permeability retention (EPR). In several preclinical studies with various tumor-bearing mice models, 188Re-liposome that has been developed by the Institute of Nuclear Energy Research (INER) demonstrates favorable in vivo tumor targeting, biodistribution, pharmacokinetics, and dosimetry. It inhibits the growth of tumors, increased survival, demonstrates good synergistic combination, and was safe to use.This study conducts a phase 0 low-radioactivity clinical trial of nano-targeted radiotherapeutics 188Re-liposome to evaluate the effectiveness with which it targets tumors and the pharmacokinetics, biodistribution, dosimetry, and its safety in use. Twelve patients with metastatic cancers are studied in this trial. Serial whole-body scans and SPECT/CT are taken at 1, 4, 8, 24, 48, and 72 h after intravenous injection of 111 MBq of 188Re-liposome. The effectiveness with which tumors are targeted, the pharmacokinetics, biodistribution, dosimetry, and safety are evaluated using the VelocityAI and OLINDA/EXM software. Blood samples are collected at different time points for a pharmacokinetics study and a safety evaluation that involves monitoring changes in liver, renal, and hematological functions.ResultsThe T½z for 188Re-liposome in blood and plasma are 36.73 ± 14.00 h and 52.02 ± 45.21 h, respectively. The doses of radiation that are absorbed to vital organs such as the liver, spleen, lung, kidney, and bone marrow are 0.92 ± 0.35, 1.38 ± 1.81, 0.58 ± 0.28, 0.32 ± 0.09, and 0.06 ± 0.01 mGy/MBq, respectively, which is far less than the reference maximum tolerance dose after injection of 188Re-liposome. 188Re-liposome is absorbed by metastatic tumor lesions and the normal reticuloendothelial (RES) system. Certain patients exhibit a therapeutic response.ConclusionThis phase 0 exploratory IND study shows that nanocarrier 188Re-liposome achieves favorable tumor accumulation and tumor to normal organ uptake ratios for a subset of cancer patients. The clinical pharmacokinetic, biodistribution, and dosimetry results justify a further dose-escalating phase 1 clinical trial.Trial registrationTaiwan FDA MA1101G0 (Jan 31, 2012).

Preparation, Characterization, and in Vitro/in Vivo Evaluation of Paclitaxel-Bound Albumin-Encapsulated Liposomes for the Treatment of Pancreatic Cancer.

Paclitaxel (PTX)-loaded liposomes were developed with the goal of enhancing the effects of cancer treatment. Although loading substances into the lipid membrane of liposome cause some destabilization of the lipid membrane, PTX was nearly exclusively embedded in the lipid membrane of liposomes, due to its low water solubility. Hydrophobic drugs can be encapsulated into the inner core of bovine serum albumin (BSA)-encapsulated liposomes (BSA-liposome) via noncovalent binding to albumin. Since PTX is able to noncovalently bind to albumin, we attempted to prepare PTX-loaded BSA-liposome (PTX–BSA-liposome). The amount of PTX loaded in the BSA-liposome could be increased substantially by using ethanol, since ethanol increases PTX solubility in BSA solutions via prompting the binding PTX to BSA. On the basis of the results of transmission electron microscopy and small-angle X-ray scattering, PTX–BSA-liposome formed unilamellar vesicles that were spherical in shape and the PTX was encapsulated into the inner aqueous core of the liposome as a form of PTX–BSA complex. In addition, the PTX–BSA-liposome, as well as nab-PTX, showed cytotoxicity against human pancreatic cancer cells, AsPC-1 cells, in a PTX concentration-dependent manner. The in vivo antitumor effect of PTX–BSA-liposomes was also observed in a mouse model that had been subcutaneously inoculated with pancreatic cancer cells by virtue of its high accumulation at the tumor site via the enhanced permeability retention effect. These results suggest that PTX–BSA-liposomes have the potential for serving as a novel PTX preparation method for the treatment of pancreatic cancer.

RGD-modified nanoliposomes containing quercetin for lung cancer targeted treatment.

PurposeThe aim of this study was to prepare RGD-modified nanoliposomes containing quercetin (QCT) distearoyl-L-a-phosphatidylethanolamine-polyethylene glycol 2000-RGD-liposomes ([DSPE]-PEG2000-RGD-LPs/QCT) for lung cancer targeting treatment.MethodsThe physicochemical parameters of (DSPE)-PEG2000-RGD-LPs/QCT were characterized in terms of the particle size, zeta potential, morphology, entrapment efficiency, drug loading, and in vitro release behavior. In vivo, pharmacokinetics and antitumor studies of prepared formulations were also evaluated.ResultsIn this study, QCT was found to be easily dispersed in lipid solution and entrapped by the thin-film hydration method. The encapsulation ratio and drug loading of prepared LPs were 89.2%±7.4% and 9.2%±1.3% and the mean diameter was 93.4±7.2 nm from 3 batches. The results of in vitro experiments showed that the particle size of liposomes was suitable for the fenestrated vasculatures of cancer tissues via the enhanced permeability retention effect. In vitro, a relatively slow QCT release profile was observed in (DSPE)-PEG2000-RGD-LPs, and the release mechanism fit with the Higuchi equation better. In vivo imaging results indicated that RGD-modified LPs had very good tumor targeting ability. (DSPE)-PEG2000-RGD-LPs/QCT showed a significant antitumor activity in mice with A549 tumors.ConclusionThrough this study, it was found that the RGD-modified LPs loaded with QCT could potentially be a very promising lung-targeted preparation.

In vivo drug delivery efficiency of albumin-encapsulated liposomes as hydrophobic drug carriers

A liposome containing encapsulated bovine serum albumin (BSA-liposome) was developed for use as a hydrophobic carrier in which hydrophobic drugs are encapsulated into the inner aqueous core of the liposome by binding to BSA. We prepared a tacrolimus (TAC)-loaded BSA-liposome (TAC-BSA-liposome) and investigated the efficiency of delivery of the encapsulated hydrophobic drug using experimental colitis model mice induced by dextran sulfate sodium (DSS). The encapsulation efficiency of TAC was dramatically increased when the BSA-liposome was used compared to an ordinary liposome (without BSA) because of the increased water solubility of TAC as the result of its binding to BSA. In in vivo biodistribution tests in DSS-induced colitis model mice, the BSA-liposome passively targeted inflammatory lesions in the colon by virtue of the well-regulated physicochemical properties (size and PEGylation) of the BSA-liposome, which is due to the enhanced permeability and retention effect. Furthermore, the intravenous administration of TAC-BSA-liposome exerted therapeutic effects against colitis in DSS-induced colitis model mice, indicating that the BSA-liposome functions as a TAC carrier in vivo. These results suggest that the BSA-liposome has the potential for delivering many kinds of albumin-bound hydrophobic drugs to inflammatory lesions or tumor sites by virtue of the enhanced permeability retention effect.

Evans Blue Derivative-Functionalized Gold Nanorods for Photothermal Therapy-Enhanced Tumor Chemotherapy.

Chemotherapy is a standard care for cancer management, but the lack of tumor targeting and high dose-induced side effects still limit its utility in patients. Here, we report a chemotherapy combined with photothermal therapy (PTT) for enhanced cancer ablation by functionalization of gold nanorods (GNRs) with a novel small molecule named truncated Evans blue (tEB). On the basis of the high binding affinity of tEB with albumin, an Abraxane-like nanodrug, human serum albumin/hydroxycamptothecin (HSA/HCPT), was further complexed with GNR-tEB. This formed an HCPT/HSA/tEB-GNR (HHEG) with excellent biostability and biocompatibility. With photoacoustic and fluorescence imaging, we observed HHEG tumor targeting, which is mediated by enhanced permeability retention effect. The accumulation of HHEG peaked in tumor at 12 h postinjection. Moreover, HHEG can effectively ablate tumor growth with laser illumination via chemo/thermal therapy after intravenous administration into SCC7 tumor. This combination is much better than chemotherapy or PTT alone. Collectively, we constructed a chemo/thermal therapy nanostructure based on a tEB-modified GNR for better tumor treatment effect. The use of tEB in gold nanoparticles can facilitate many new approaches to design hybrid nanoparticles.

AB011. 175. Selective colorectal cancer fluorescence by calibrated dose and timing of indocyanine green with standard near-infrared endoscopic illumination alone

: Confident, optical discrimination of malignant from benign tissue within the colorectum could be useful during colonoscopy for the easy identification of live cancer cell deposits within neoplastic sites. We show how the enhanced permeability retention (EPR) phenomenon, a hallmark characteristic of cancer, can be reliably exploited by intelligent dose-delay utilization of near infrared (NIR) with indocyanine green (ICG) providing for endoscopic visualization of colorectal cancer tissue with high selectivity versus background, adjacent non-neoplastic tissue. NIR viewing was achieved using the PINPOINT Endoscopic System (Novadaq) for NIR illumination. ICG was administered as a systemic aliquot via peripheral cannula at a dose of 0.25 mg/kg and the region of interest visualized 15 minutes afterwards. Careful dose/interval combination induces primary tumour fluorescence in a variety of settings including direct serosal visualisation of colonic cancers in both open and laparoscopic surgery and identification of out-of field metastatic relapse in the retroperitoneum in a patient after prior radical D3 resection of a right colon cancer. Prior dose-related work has shown that earlier administration (40–180 minutes before examination) gives no useful tumour fluorescence. Targeting the tumour microenvironment as a package obviates the issue of variable expression cellular phenotypes while use of a safe and approved agent avoids toxicity concerns and allows clinicians focus on determination of clinical usefulness including indicative cost-economic profiling ahead of new agent commercialisation. In this way, NIR-ICG offers itself as a similar oncologic diagnostic modality as FDG-PET while remaining the benchmark fluorescent agent for intraoperative tissue evaluation.

Brain- and brain tumor-penetrating disulfiram nanoparticles: Sequence of cytotoxic events and efficacy in human glioma cell lines and intracranial xenografts

There is great interest in repurposing disulfiram (DSF), a rapidly metabolizing nontoxic drug, for brain cancers and other cancers. To overcome the instability and low therapeutic efficacy, we engineered passively-targeted DSF-nanoparticles (DSFNPs) using biodegradable monomethoxy (polyethylene glycol) d,l-lactic-co-glycolic acid (mPEG-PLGA) matrix. The physicochemical properties, cellular uptake and the blood brain-barrier permeability of DSFNPs were investigated. The DSFNPs were highly stable with a size of ∼70 nm with a >90% entrapment. Injection of the nanoparticles labeled with HITC, a near-infrared dye into normal mice and tumor-bearing nude mice followed by in vivo imaging showed a selective accumulation of the formulation within the brain and subcutaneous tumors for >24 h, indicating an increased plasma half-life and entry of DSF into desired sites. The DSFNPs induced a potent and preferential killing of many brain tumor cell lines in cytotoxicity assays. Confocal microscopy showed a quick internalization of the nanoparticles in tumor cells followed by initial accumulation in lysosomes and subsequently in mitochondria. DSFNPs induced high levels of ROS and led to a marked loss of mitochondrial membrane potential. Activation of the MAP-kinase pathway leading to a nuclear translocation of apoptosis-inducing factor and altered expression of apoptotic and anti-apoptotic proteins were also observed. DSFNPs induced a powerful and significant regression of intracranial medulloblastoma xenografts compared to the marginal efficacy of unencapsulated DSF. Together, we show that passively targeted DSFNPs can affect multiple targets, trigger potent anticancer effects, and can offer a sustained drug supply for brain cancer treatment through an enhanced permeability retention (EPR).

Theranostic Hyaluronic Acid-Iron Micellar Nanoparticles for Magnetic-Field-Enhanced in vivo Cancer Chemotherapy.

The delivery of therapeutic cancer agents using nanomaterials has recently attracted much attention. Although encouraging progress with chemotherapeutics has been made, tumor treatment response remains unsatisfactory. To address this concern, we constructed a new micellar nanocomplex by covalently conjugating hyaluronic acid (HA) with an iron oxide nanoparticle (IONP). When an external magnetic field was applied to the tumor area, HA-IONP specifically accumulated in the tumor, due to the strong IONP magnetism. In addition, HA was shown to bind to cluster determinant 44 (CD44), which is overexpressed on tumor cells. With combined magnetic, CD44, and enhanced permeability retention (EPR) targeting, the efficient delivery of HA-IONP to the tumor is expected to enhance cancer treatment efficiency. After encapsulation of the chemotherapy drug homocamptothecin (HCPT), the theranostic potency of HA-IONP/HCPT (HIH) was investigated both in vitro and in vivo. The improved tumor homing behavior of HIH was observed by magnetic resonance imaging (MRI) when an external magnetic field was used. Moreover, HIH showed remarkable tumor ablation efficiency, with magnetic targeting after 3 mg kg-1 intravenous administration (equivalent dose of free HCPT), and the tumors almost disappeared after treatment. No obvious systemic toxicity was detected. This excellent biocompatibility and tumor targetability suggests that HIH is a promising theranostic nanocomplex with great translational potency. Application of the HA-IONP platform could also be extended to delivery of other hydrophobic chemotherapy drugs or phototherapy agents.