Effective Tumor Targeting Research Articles

Renal-Clearable Peptide-Functionalized Ba2GdF7 Nanoparticles for Positive Tumor-Targeting Dual-Mode Bioimaging.

Considering the dilemma between the effective tumor targeting and the avoidance of potential toxicity, it is desired to design nanoprobes with positive tumor-targeting and good renal clearance ability. In the present work, we developed epidermal growth factor receptor (EGFR)-targeted peptide-functionalized Ba2GdF7 nanoparticles (termed as pEGFR-targeted Ba2GdF7 NPs) for positive tumor-targeting magnetic resonance imaging and X-ray computed tomography (MRI/CT) dual-mode bioimaging. The positive tumor-targeting ability of pEGFR-targeted Ba2GdF7 NPs is achieved by conjugation of EGFR-targeted peptides on the 6.5 nm Ba2GdF7 NP surface through the formation of Gd-phosphonate coordinate bonds. The pEGFR-targeted Ba2GdF7 NPs display desirable cytocompatibility in the test concentration range and high binding affinity with lung cancer cells. In vivo MR and CT imaging results demonstrate that the pEGFR-targeted Ba2GdF7 NPs are able to be accumulated and detained within an engrafted A549 lung carcinoma, which enhances both MR and CT contrast in the tumor tissue. Systematic in vivo experimental results further demonstrate that the pEGFR-targeted Ba2GdF7 NPs have favorable in vivo renal clearance kinetics as well as reasonable in vivo biocompatibility.

Abstract 4120: A novel HDAC-targeted probe for triple-negative breast tumor imaging

Abstract Purpose: Due to lack of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER-2), there was no specific imaging probes can be applied to detect triple-negative breast cancers (TNBCs). Currently, several lines of evidences support that overexpression of histone deacetylases (HDACs) has been associated with TNBC. Here, we sought to develop HDAC-targeted probe for TNBC imaging. Experimental Design: The pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) was chosen as the targeting ligand, and was labeled with a near-infrared dye IRDye800CW for the development of HDAC-targeted probe IRDye800CW-SAHA. Subsequently, HDAC binding affinity and specificity of probe IRDye800CW-SelSA to TNBC MDA-MB-231 cells was evaluated by HDAC inhibition assay, flow cytometry and confocal laser microscope experiments. Moreover, the in vivo fluorescence molecular imaging (FMI) was performed to monitor the biodistribution and tumor targeting effects of the probe in MDA-MB-231 tumor xenografts. Results: The fluorescence probe IRDye800CW-SAHA was successfully developed, and conjugating IRDye800CW to SAHA did not alter the HDAC binding affinity. The cellular uptake and the fluorescence intensity of probe on MDA-MB-231 cells were significantly higher compared to normal MCF-10A cells (P < 0.05). Meanwhile, the cellular uptake of probe can be effectively blocked by co-incubation with SAHA. The in vivo imaging results showed that IRDye800CW-SelSA was able to target tumor rapidly, and the tumor to normal tissue (T/N) fluorescence intensity ratio reached the peak around 12 h (T/N = 3.4). Conclusions: Our study demonstrated that IRDye800CW-SAHA is an efficient probe for the targeted imaging of TNBC and may possess clinical translation in the future. CT and YD contributed equally to this work Citation Format: Chu Tang, Yang Du, Jie Tian. A novel HDAC-targeted probe for triple-negative breast tumor imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4120.

Targeting the TGF\u03b2 pathway with galunisertib, a TGF\u03b2RI small molecule inhibitor, promotes anti-tumor immunity leading to durable, complete responses, as monotherapy and in combination with checkpoint blockade

BackgroundTGFβ signaling plays a pleotropic role in tumor biology, promoting tumor proliferation, invasion and metastasis, and escape from immune surveillance. Inhibiting TGFβ’s immune suppressive effects has become of particular interest as a way to increase the benefit of cancer immunotherapy. Here we utilized preclinical models to explore the impact of the clinical stage TGFβ pathway inhibitor, galunisertib, on anti-tumor immunity at clinically relevant doses.ResultsIn vitro treatment with galunisertib reversed TGFβ and regulatory T cell mediated suppression of human T cell proliferation. In vivo treatment of mice with established 4T1-LP tumors resulted in strong dose-dependent anti-tumor activity with close to 100% inhibition of tumor growth and complete regressions upon cessation of treatment in 50% of animals. This effect was CD8+ T cell dependent, and led to increased T cell numbers in treated tumors. Mice with durable regressions rejected tumor rechallenge, demonstrating the establishment of immunological memory. Consequently, mice that rejected immunogenic 4T1-LP tumors were able to resist rechallenge with poorly immunogenic 4 T1 parental cells, suggesting the development of a secondary immune response via antigen spreading as a consequence of effective tumor targeting. Combination of galunisertib with PD-L1 blockade resulted in improved tumor growth inhibition and complete regressions in colon carcinoma models, demonstrating the potential synergy when cotargeting TGFβ and PD-1/PD-L1 pathways. Combination therapy was associated with enhanced anti-tumor immune related gene expression profile that was accelerated compared to anti-PD-L1 monotherapy.ConclusionsTogether these data highlight the ability of galunisertib to modulate T cell immunity and the therapeutic potential of combining galunisertib with current PD-1/L1 immunotherapy.

Human GUCY2C-Targeted Chimeric Antigen Receptor (CAR)-Expressing T Cells Eliminate Colorectal Cancer Metastases.

One major hurdle to the success of adoptive T-cell therapy is the identification of antigens that permit effective targeting of tumors in the absence of toxicities to essential organs. Previous work has demonstrated that T cells engineered to express chimeric antigen receptors (CAR-T cells) targeting the murine homolog of the colorectal cancer antigen GUCY2C treat established colorectal cancer metastases, without toxicity to the normal GUCY2C-expressing intestinal epithelium, reflecting structural compartmentalization of endogenous GUCY2C to apical membranes comprising the intestinal lumen. Here, we examined the utility of a human-specific, GUCY2C-directed single-chain variable fragment as the basis for a CAR construct targeting human GUCY2C-expressing metastases. Human GUCY2C-targeted murine CAR-T cells promoted antigen-dependent T-cell activation quantified by activation marker upregulation, cytokine production, and killing of GUCY2C-expressing, but not GUCY2C-deficient, cancer cells in vitro GUCY2C CAR-T cells provided long-term protection against lung metastases of murine colorectal cancer cells engineered to express human GUCY2C in a syngeneic mouse model. GUCY2C murine CAR-T cells recognized and killed human colorectal cancer cells endogenously expressing GUCY2C, providing durable survival in a human xenograft model in immunodeficient mice. Thus, we have identified a human GUCY2C-specific CAR-T cell therapy approach that may be developed for the treatment of GUCY2C-expressing metastatic colorectal cancer. Cancer Immunol Res; 6(5); 509-16. ©2018 AACR.

Double-Targeting Explosible Nanofirework for Tumor Ignition to Guide Tumor-Depth Photothermal Therapy.

This study reports a double-targeting "nanofirework" for tumor-ignited imaging to guide effective tumor-depth photothermal therapy (PTT). Typically, ≈30 nm upconversion nanoparticles (UCNP) are enveloped with a hybrid corona composed of ≈4 nm CuS tethered hyaluronic acid (CuS-HA). The HA corona provides active tumor-targeted functionality together with excellent stability and improved biocompatibility. The dimension of UCNP@CuS-HA is specifically set within the optimal size window for passive tumor-targeting effect, demonstrating significant contributions to both the in vivo prolonged circulation duration and the enhanced size-dependent tumor accumulation compared with ultrasmall CuS nanoparticles. The tumors featuring hyaluronidase (HAase) overexpression could induce the escape of CuS away from UCNP@CuS-HA due to HAase-catalyzed HA degradation, in turn activating the recovery of initially CuS-quenched luminescence of UCNP and also driving the tumor-depth infiltration of ultrasmall CuS for effective PTT. This in vivo transition has proven to be highly dependent on tumor occurrence like a tumor-ignited explosible firework. Together with the double-targeting functionality, the pathology-selective tumor ignition permits precise tumor detection and imaging-guided spatiotemporal control over PTT operation, leading to complete tumor ablation under near infrared (NIR) irradiation. This study offers a new paradigm of utilizing pathological characteristics to design nanotheranostics for precise detection and personalized therapy of tumors.

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.

Near-infrared fluorescent pyrrolopyrrole cyanine derivatives and colloidal nanoparticles with tunable optical properties for in vivo bioimaging

Near infrared (NIR) fluorescent molecules with light absorption and emission above 700 nm are important for noninvasive and deep-tissue imaging for disease diagnosis and imaging-guided surgery. Nevertheless, currently available NIR fluorophores with high fluorescence quantum yields and robust photostability remain rather limited. Here we report a series of π-extended pyrrolopyrrole cyanine (PPCy) derivatives with tunable light absorption and emission in the NIR spectral region. The extent of the intramolecular charge transfer shows significant effect on the optical bandgap, the Stokes shift and the fluorescence quantum yield. These hydrophobic PPCy derivatives were dispersed as colloidal nanoparticles into water via a nanoprecipitation process. The nanoparticles composed of spirofluorene-flanked PPCy derivatives exhibit the optimal optical properties, effective tumor-targeting, and high fluorescence contrast for in vivo bioimaging of xenografted tumor-model mice.

Transferrin-Modified Vitamin-E/Lipid Based Polymeric Micelles for Improved Tumor Targeting and Anticancer Effect of Curcumin.

Transferrin receptor (TfR) is up-regulated in various malignant tumors not only to meet the iron requirement, but also to increase the cell survival via participation in various cellular signaling pathways. Here we explored transferrin as ligand for Poly(ethylene Glycol) (PEG)-ylated vitamin-E/lipid (PE) core micelles (VPM). Transferrin modified polymer was synthesized and drug loaded micelles were evaluated in 2D Hela and HepG2 cancer cells for cellular uptake and cytotoxicity and in 3D Hela spheroids for growth inhibition, uptake and penetration studies. Targeted (Tf-VPM) and non-targeted (VPM) micelles showed mean hydrodynamic diameter of 114.2 ± 0.64nm and 117.4 ± 0.72nm and zeta potential was -22.8 ± 0.62 and -14.8 ± 1.74mV, respectively. Cellular uptake study indicated that the Tf-CVPM were taken up by cancer cells (Hela and HepG2) with higher efficiency. Enhanced cytotoxicity was demonstrated for Tf-VPM compared to CVPM. Marked spheroid growth inhibition following treatment with Tf-CVPM was observed compared to the treatment with non-targeted CVPM. The developed transferrin-modified micelles have improved ability to solubilize the loaded drugs and could actively target solid tumors by its interaction with over-expressed transferrin receptors. Therefore, the nano-micelles could be further explored for its potential utilization in cancer therapy.

Construction and application of a liver cancer-targeting drug delivery system based on core-shell gold nanocages.

BackgroundIn order to achieve drug targeting and controlled release, we have successfully developed a novel drug release system DOX/AuNCs-PM-HA with gold nanocages (AuNCs) as photothermal cores, thermally responsive copolymer P(NIPAM-co-Am) (PM) as the near-infrared (NIR) stimuli gatekeeper and hyaluronic acid as a targeting ligand as well as a capping agent.MethodsCell uptake and cell viability were investigated. In vivo photoacoustic tomography imaging in H22 tumor bearing mice was analyzed for the tumor targeting effect of the nanocomplexes. Antitumor efficacy and the tissue distribution in vivo were investigated.ResultsIn vitro results demonstrated that the DOX/AuNCs-PM-HA had significant anticancer activity against SMMC-7721 cells under NIR irradiation. Furthermore, in vivo photoacoustic tomography imaging of the nanocomplexes in H22 tumor bearing mice could indicate effective tumor targeting. Our studies on antitumor efficacy and the tissue distribution in vivo showed that many DOX/AuNCs-PM-HA nanocomplexes could efficiently accumulate at the tumor site so that they could inhibit the tumor growth effectively with limited side effects. The in vitro and in vivo results confirmed that the tumor-targeting and controlled-release drug system DOX/AuNCs-PM-HA with the combination of chemotherapy and photothermal therapy showed strong anti-tumor effect and would have great potential for future cancer therapy.ConclusionThis tumor targeting DOX/AuNCs-PM-HA nanocomplex responded not only to the external stimuli of NIR, but also the internal stimuli of hyaluronidase, providing the potential for pinpointed and multi-stimuli responsive intracellular drug release.

SiRNA-loaded selenium nanoparticle modified with hyaluronic acid for enhanced hepatocellular carcinoma therapy.

BackgroundSmall interfering RNA (siRNA) as a new therapeutic modality holds promise for cancer treatment. However, the traditional viral carriers are prone to immunogenicity and risk of insertional mutagenesis.MethodsIn order to provide a tumor-targeted delivery carrier of siRNA in cancer therapy, the hyaluronic acid (HA)-selenium (Se)-polyethylenimine (PEI) nanoparticle (NP) was fabricated by decorating SeNP with HA as a tumor-targeting moiety and by linking the polycationic polymers polyethylenimine PEI onto the surface of SeNP. The siRNA was loaded to the surface of SeNP HA-Se-PEI via the electrostatic interaction between siRNA and PEI to prepare the functionalized SeNP HA-Se-PEI@siRNA.ResultsThe HA-Se-PEI@siRNA was internalized into the HepG2 cell mainly in a clathrin-mediated endocytosis manner. Owing to the active tumor-targeted effect mediated by HA, HA-Se-PEI@siRNA achieved the obvious higher transfection efficiency, greater gene silencing ability, and stronger cytotoxicity in the HepG2 cell compared with the passive tumor-targeted NP Se-PEI@siRNA. The knockdown of hairy and enhancer of split 5 by HA-Se-PEI@siRNA induced the HepG2 cell cycle arrest at the G0/G1 phase and apoptosis. Furthermore, the treatment with HA-Se-PEI@siRNA resulted in greater antitumor efficacy compared with the Se-PEI@siRNA in vitro and in vivo. In addition, the HA-Se-PEI@siRNA was almost no toxic to the key organs of mice.ConclusionThese findings provided an alternative therapeutic route for targeted cancer treatments.

Recent Advances in Polymeric Nanosystems for Treating Cutaneous Melanoma and Its Metastasis.

Melanoma shows a high possibility of mortality after it metastasizes because of its aggressive nature. Although there are several options for anti-melanoma therapy, this skin malignancy is resistant to some therapies. Chemotherapy, biochemotherapy, immunotherapy, and adoptive cell therapy have failed to exhibit a significant amelioration in overall survival. Nanomedicine provides an opportunity to improve the efficiency of the antimelanoma regimen. Nanoparticles for treating melanoma provide the advantages over conventional therapies such as drug solubility increment, drug stability enhancement, epithelium permeability and bioavailability amelioration, half-life prolonging, tumor targeting, and side effect minimization. Polymeric nanocarriers are the most extensively studied platforms for the treatment of a variety of cancers. The polymers' sophisticated material engineering tailors the controllable physicochemical properties of the nanoparticles for melanoma penetration via passive and active delivery. The present study highlights the recent progress on the development of polymeric nanoparticles for melanoma treatment. We describe the concepts and improvement mechanisms of the nanomedical techniques for melanoma treatment. Passive targeting by modifying the structure and physicochemical characters of polymeric nanocarriers is a strategy for efficient drug delivery to the melanoma and its metastasis. On the other hand, active targeting such as peptide or antibody conjugation is another approach delivering the drugs or genes to the nidus site by the nanocarriers. This review offers an overview of the benefits of polymeric nanosystems for treating melanoma.

Lysosome-Independent Intracellular Drug/Gene Codelivery by Lipoprotein-Derived Nanovector for Synergistic Apoptosis-Inducing Cancer-Targeted Therapy.

In this paper, reconstituted high-density lipoprotein (rHDL), a lipoprotein-derived nanovector, was constructed for codelivery of paclitaxel (PTX) and wild-type p53 gene (p53). The particle size and the zeta potential of PTX-DODAB/p53-rHDL nanoparticles were 177.2 nm and -20.06 mV, respectively. Meanwhile, they exhibited great serum stability and satisfactory sustained release characteristics in vitro. PTX-DODAB/pDNA-rHDL nanoparticles simultaneously improved the cellular uptake of PTX and pDNA via scavenger receptor B type I (SR-BI) mediated lysosome-independent internalization and promoted the transfection of pDNA in MCF-7 cells, which were revealed by flow cytometry and confocal laser scanning microscopy analyses. The high p53 protein expression in MCF-7 cells after rHDL-mediated transfection was detected by Western blotting assay. Moreover, PTX-DODAB/p53-rHDL nanoparticles showed superior cytotoxicity and significantly induced apoptosis in SR-BI overexpressed MCF-7 cells. In in vivo studies, PTX-DODAB/p53-rHDL nanoparticles without obvious toxic effects to vessels, blood, or major organs exhibited efficient tumor targeting and encouraging antitumor effects on tumor-bearing nude mice compared with controls. All the results above indicated that PTX-DODAB/p53-rHDL nanoparticles held broad prospects in combination of chemotherapeutics and gene therapeutic agents for cancer-targeted therapy.

Peptide nanosponges designed for rapid uptake by leukocytes and neural stem cells.

The structure of novel binary nanosponges consisting of (cholesterol-(K/D)nDEVDGC)3-trimaleimide units possessing a trigonal maleimide linker, to which either lysine (K)20 or aspartic acid (D)20 are tethered, has been elucidated by means of TEM. A high degree of agreement between these findings and structure predictions through explicit solvent and then coarse-grained molecular dynamics (MD) simulations has been found. Based on the nanosponges' structure and dynamics, caspase-6 mediated release of the model drug 5(6)-carboxyfluorescein has been demonstrated. Furthermore, the binary (DK20) nanosponges have been found to be virtually non-toxic in cultures of neural progenitor cells. It is of a special importance for the future development of cell-based therapies that DK20 nanosponges were taken up efficiently by leucocytes (WBC) in peripheral blood within 3 h of exposure. The percentage of live cells among the WBC was not significantly decreased by the DK20 nanosponges. In contrast to stem cell or leucocyte cell cultures, which have to be matched to the patient, autologous cells are optimal for cell-mediated therapy. Therefore, the nanosponges hold great promise for effective cell-based tumor targeting.

Synthesis and in vitro experiments of carcinoma vascular endothelial targeting polymeric nano-micelles combining small particle size and supermagnetic sensitivity

Objective: To construct carcinoma vascular endothelial-targeted polymeric nanomicelles with high magnetic resonance imaging (MRI) sensitivity and to evaluate their biological safety and in vitro tumor-targeting effect, and to monitor their feasibility using clinical MRI scanner.Method: Amphiphilic block copolymer, poly(ethylene glycol)-b-poly(ε-caprolactone) (PEG-PCL) was synthesized via the ring-opening polymerization of ε-caprolactone (CL) initiated by poly(ethylene glycol) (PEG), in which cyclic pentapeptide Arg-Gly-Asp (cRGD) was conjugated with the terminal of hydrophilic PEG block. During the self-assembly of PEG-PCL micelles, superparamagnetic γ-Fe2O3 nanoparticles (11 nm) was loaded into the hydrophobic core. The cRGD-terminated γ-Fe2O3-loaded polymeric micelles targeting to carcinoma vascular endothelial cells, were characterized in particle size, morphology, loading efficiency and so on, especially high MRI sensitivity in vitro. Normal hepatic vascular endothelial cells (ED25) were incubated with the resulting micelles for assessing their safety. Human hepatic carcinoma vascular endothelial cells (T3A) were cultured with the resulting micelles to assess the micelle uptake using Prussian blue staining and the cell signal intensity using MRI.Results: All the polymeric micelles exhibited ultra-small particle sizes with approximately 50 nm, high relaxation rate, and low toxicity even at high iron concentrations. More blue-stained iron particles were present in the targeting group than the non-targeting and competitive inhibition groups. In vitro MRI showed T2WI and T2 relaxation times were significantly lower in the targeting group than in the other two groups.Conclusion: γ-Fe2O3-loaded PEG-PCL micelles not only possess ultra-small size and high superparamagnetic sensitivity, also can be actively targeted to carcinoma vascular endothelial cells by tumor-targeted cRGD. It appears to be a promising contrast agent for tumor-targeted imaging.

Targeted delivery of ginsenoside compound K using TPGS/PEG-PCL mixed micelles for effective treatment of lung cancer

Ginsenoside compound K (CK) is one of the effective ingredients in antitumor composition of ginsenoside. However, the poor water solubility and significant efflux have limited the widespread clinical use of CK. In this study, preparation of novel CK-loaded d-alpha-tocopheryl polyethylene glycol 1,000 succinate/poly(ethylene glycol)-poly(ε-caprolactone) mixed micelles (CK-M) is discussed to solve the above problems. Particle size, zeta potential, and morphology were characterized using dynamic light scattering and transmission electron microscopy. CK-M are spherical shaped with an average particle size of 53.07±1.31 nm with high drug loading of 11.19%±0.87% and entrapment efficiency of 94.60%±1.45%. Water solubility of CK was improved to 3.78±0.09 mg/mL, which was ~107.35 times higher than free CK. A549 and PC-9 cells were used to evaluate in vitro cytotoxicity and cellular uptake. IC50 values of CK-M in A549 and PC-9 cells (24 h) were 25.43±2.18 and 18.35±1.90 μg/mL, respectively. Enhanced cellular uptake of CK-M was observed in both cells. Moreover, CK-M promoted tumor cell apoptosis, inhibited tumor cell invasion, metastasis, and efflux through regulation of Bax, Bcl-2, matrix metalloproteinase-2, Caspase-3, and P-glycoprotein. In vivo imaging indicated that CK-M has excellent tumor targeting effect within 24 h, and the relative tumor inhibition rate of CK-M was 52.04%±4.62% compared with control group (P<0.01). Thus, CK-M could be an appropriate delivery agent for enhanced solubility and antitumor effect of CK.

Multi-functionalized polymeric nanoparticles realized enhanced drug loading efficiency, extended circulation time, and significant in vivo tumor targeting effect

Multi-functionalized polymeric nanoparticles realized enhanced drug loading efficiency, extended circulation time, and significant in vivo tumor targeting effect

Gold Nanoclusters-Indocyanine Green Nanoprobes for Synchronous Cancer Imaging, Treatment, and Real-Time Monitoring Based on Fluorescence Resonance Energy Transfer.

Well-designed gold nanoclusters-indocyanine green nanoprobes (Au NCs-INPs) have been developed by the conjugation of Au NC assemblies with indocyanine green (ICG) for the therapeutic real-time monitoring based on fluorescence resonance energy transfer (FRET). The synthesized Au NCs-INPs demonstrated the improved cellular uptake and effective tumor targeting because of the enhanced permeability and retention effect and the gp60-mediated secreted protein acidic and rich in cysteine combined transport pathway, suggesting excellent dual-modal near-infrared fluorescence and photoacoustic imaging. Moreover, the simultaneous photodynamic therapy (PDT) and photothermal therapy (PTT) of Au NCs-INPs exhibited higher cancer cell killing and tumor removal efficiency than those of PDT or PTT alone. More importantly, a promising therapeutic monitoring strategy was performed based on FRET between Au NCs and ICG, suggesting that Au NCs-INPs could be utilized to evaluate the therapeutic response by real-time monitoring the change in Au NCs in fluorescence intensity together with ICG supersession. Therefore, Au NCs-INPs as a novel photosensitizer have great potentials for combined tumor imaging, therapy, and therapeutic monitoring in real time.

Abstract 2196: SDF-1/CXCR4 axis-mediated tumor-tropism of monocyte membrane-coated nanoparticles

Abstract Tumor-associated macrophages are one of the most abundant infiltrating cells in solid tumors. These cells are originated from the bone marrow and circulating in peripheral blood. Through the specific chemoattractant released by the tumor cells or stromal cells, bone marrow-derived monocytes (BMDMs) are able to accumulate at the tumor site by their corresponding receptors. In this study, we utilized the characteristics of tumor-tropism of BMDMs on a nanoparticle-based drug delivery system. We hypothesized that the cellular membrane of BMDMs can provide nanoparticle protection from the mononuclear phagocyte system and the chemokine receptor on the membrane can enhance the tumor-tropism of the nanoparticles. To prove the hypothesis, the cellular membrane was extracted from BMDMs and then coated on the drug-loaded nanoparticles. We also found that the expression of chemokine receptor CXCR4 on the bone BMDMs can be induced following the stimulation of tumor conditioned medium. The tumor targeting effect of the monocyte membrane-coated nanoparticles is diminished against SDF-1 knockdown tumor cells. These results indicate that the SDF-1/CXCR4 axis is contributed to the tumor-tropism of the monocyte membrane-coated nanoparticles toward astrocytoma cell line, ALTS1C1, and this effect can be boosted by the stimulation of tumor conditioned medium. In conclusion, we established a nanoparticle-based drug delivery platform against brain tumor with the cellular membrane coating technology and maximized the effect of tumor-targeting by tumor conditioned medium stimulation. Citation Format: Yi-Nan Li, Chien-Wen Chang, Chi-Shiun Chiang. SDF-1/CXCR4 axis-mediated tumor-tropism of monocyte membrane-coated nanoparticles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2196. doi:10.1158/1538-7445.AM2017-2196

Mussel-Inspired Hyaluronic Acid Derivative Nanostructures for Improved Tumor Targeting and Penetration.

An amphiphilic hyaluronic acid-ceramide-dopamine (HACE-d) conjugate was prepared, and HACE-d-based nanoparticles (NPs) including phloretin (as an inhibitor of glucose transporter (GLUT1)) were fabricated. Mussel-inspired property of d was introduced to HACE NPs, and it may improve tumor targetability and penetration in addition to passive (based on enhanced permeability and retention effect) and active (interaction between HA and CD44 receptor) tumor targeting effects. HACE-d/phloretin NPs with 279 nm mean diameter, ∼0.2 polydispersity index, and -18 mV zeta potential were successfully fabricated, and a sustained drug release pattern was observed. HACE-d/phloretin NPs exhibited enhanced cellular accumulation efficiency and antiproliferation property, compared with HACE/phloretin NPs, in MDA-MB-231 cells (GLUT1 and CD44 receptor-expressed human breast adenocarcinoma cells). In a MDA-MB-231 spheroid model, HACE-d NPs group showed better tumor penetration efficiency and spheroid growth inhibitory effect rather than HACE NPs group. According to the optical imaging test in MDA-MB-231 tumor-xenografted mouse, HACE-d NPs group exhibited more selective distribution in tumor region and deeper infiltration into the inner part of tumor compared with HACE NPs group. After intravenous injection, HACE-d/phloretin NPs group also exhibited improved antitumor efficacies rather than the other experimental groups in MDA-MB-231 tumor-xenografted mouse. All these findings suggested that HACE-d/phloretin NP may be a promising tumor targetable and penetrable nanosystem for the therapy and imaging of GLUT1 and CD44 receptor-expressed cancers.

Lipid-insertion to enable targeting functionalization of paclitaxel loaded erythrocyte membrane nanoparticle by tumor-penetrating bispecific recombinant protein.

e14047 Background: There is a great interest in targeting and penetrating of cancer cells for research or therapeutic purposes. Red blood cells (RBCs) are readily available and fully biocompatible long-circulating intravascular carriers that are amenable to chemical modifications, drug loading and reinjection. The purpose of this study was to design a tumor-targeting biocompatible drug delivery system for delivery of antitumor drugs. Methods: DSPE-PEG-MAL, phospholipid derivatives was used to insert into erythrocyte membrane nanoparticles. To make nanoparticles active targeting to the tumor site, a tumor-penetrating bispecific recombinant protein named anti-EGFR-iRGD was used. The characterization, bio-distribution, tumor targeting ability and antitumor activity of paclitaxel loaded anti-EGFR-iRGD modified erythrocyte membrane nanoparticle were evaluated. Results: In this study, anti-EGFR-iRGD-RBC-PTX nanoparticles was successfully constructed with a size of around 100 nm. A lipid-insertion method is employed to functionalize these nanoparticles without the need for direct chemical conjugation. It showed signifcantly targeted skill and increased cytotoxic effect toward both nontargeted RBC-PTX and combination of anti-EGFR-iRGD and RBC-PTX. The tissue distribution and antitumor assays in mice bearing gastric cancer xenograft confrmed the superior penetration tumor effcacy and antitumor activity of anti-EGFR-iRGD-RBC-PTX. Conclusions: We designed and successfully prepared a novel anti-EGFR-iRGD decorated, erythrocyte membrane sourced nanoparticle for targeted drug delivery, with enhanced tumor targeting and anti-tumor effect. Anti-EGFR-iRGD-RBC-PTX represents a potential effective nanomedicine against gastric cancer.