Tumor Growth Inhibition Effect Research Articles

TIPE2 suppresses progression and tumorigenesis of the oral tongue squamous cell carcinoma by regulating FoxP3+ regulatory T cells.

To discover the effect of tumor necrosis factor-alpha-induced protein 8-like 2 (TIPE2) on the oral tongue squamous cell carcinoma (OTSCC) via affecting FoxP3+ regulatory T (Treg) cells. Immunohistochemistry was conducted to examine TIPE2 and FoxP3 expressions in OTSCC tumor tissues and corresponding oral mucosa. Tca8113 cells were transfected with TIPE2/control lentiviral activation particles followed by the detection with qRT-PCR, Western blotting, MTT assay, Wound healing, Transwell assay and Annexin V-FITC/PI staining. In vivo experiment was carried out on the nude mice xenografts of OTSCC with TIPE2 overexpression to observe the tumor volume and survival, and the CD4+ T cell subgroups were detected by flow cytometry. TIPE2 was lower in the OTSCC tissues than the corresponding oral mucosa, which was correlated with T stage, N stage, TNM stage, and differentiation of patients. Patients with TIPE2-positive expression had worse prognosis and lower expression of FoxP3+ Treg cells than the negative ones. Furthermore, TIPE2 overexpression curbed proliferation, invasion and migration of Tca8113 cells, while cell apoptosis was increased. Besides, TIPE2 suppressed the tumor growth and extended the survival of OTSCC mice, with the decreased proportion of FoxP3+ Treg cells in the spleen and tumor-infiltrated lymphocytes (TILs). The clinical results showed the down-regulation of TIPE2 in OTSCC tissues. Meanwhile TIPE2 overexpression affected OTSCC cells biological behavior in vitro, as well as exhibited strong tumor-growth suppressive effects in vivo, which may be a potential therapeutic target in OTSCC via regulating FoxP3+ Treg cells.

Sequentially-targeted biomimetic nano drug system for triple-negative breast cancer ablation and lung metastasis inhibition

As a breast cancer subtype with high mortality in women, the efficient treatment of Triple-negative breast cancer (TNBC) is still a challenge due to its unique metastatic mode and poor prognosis. In this study, we developed a biomimetic nanodelivery system (denoted as GTDC@M-R NPs) based on erythrocyte membrane (M)-camouflaged graphene oxide quantum dots (GOQDs, G) for TNBC therapy. The TAT (T) and RGD (R) peptides were used to endow targeting accumulation ability of Gamabufotalin (CS-6, C) and doxorubicin (DOX, D) in tumor tissue. In vitro assay indicated good biocompatibility, prolonged blood circulation time (3-fold longer than GT NPs), and effectively enhanced cell and nucleus targeting capability of this nanosystem. Fluorescence activated cell sorter (FACS) analysis indicated that the combination of DOX and CS-6 induced TNBC cell apoptosis more than 89 % under the ratio of 10:1. In vivo assay indicated that the accumulation of GTDC@M-R NPs in tumor sites increased about 2-fold compared to naked GTDC NPs, which was accompanied by high tumor apoptosis rates through blocking chemotherapy-activated cyclooxygenase-2 (COX-2) and enhancing DOX's anti-tumor activity of chemical drugs (85%). Moreover, comparing with the control, the average number of lung metastatic nodules in tumor-bearing mice reduced 84%, the molecular mechanism of which is related to the down expression of COX-2, matrix metalloproteinase 9 (MMP9) and vascular endothelial growth factor (VEGF). Taken together, our results proved that the developed GTDC@M-R NPs can inhibit the growth and suppress metastasis of TNBC, which broaden our insights into the application of combinational strategy for efficient TNBC therapy. Statement of SignificanceIn this study, we developed a biomimetic nanodelivery system (denoted as GTDC@M-R NPs) based on erythrocyte membrane (M)-camouflaged graphene oxide quantum dots (GOQDs, G) for TNBC therapy. The TAT (T) and RGD (R) peptides were used to endow targeting accumulation ability of Gamabufotalin (CS-6, C) and doxorubicin (DOX, D) in tumor tissue. These GTDC@M-R NPs indicated synergistic chemotherapy against TNBC cells through the precise cell and nuclear targeting, immune escape, and improved DOX sensitivity. A effective inhibition of tumor growth and metastasis was achieved by inhibiting Bcl-2/BAX, COX-2 and VEGF related signal pathways. Our finding suggests that the developed GTDC@M-R NPs present great treating effects in the preclinical models of TNBC, which broaden our insights into the application of combinational strategy for efficient TNBC therapy.

Oxygen-producing catalase-based prodrug nanoparticles overcoming resistance in hypoxia-mediated chemo-photodynamic therapy

Extreme hypoxia inside solid tumors is the primary barrier against the advance of chemotherapy and photodynamic therapy (PDT). To address this problem, a hybrid nano-enzyme prodrug system was developed to alleviate hypoxia as well as simultaneously sensitize chemo-photodynamic therapy. Lactobionic acid (LA) and doxorubicin (DOX) precursor (cis-aconitic anhydride-linked doxorubicin, CAD) were pre-conjugated onto the side chain of catalase (CAT), then co-assembled with chlorin e6 (Ce6) to form LA-CAT-CAD@Ce6 nanoparticles (LCC@Ce6-NPs). LA as the active-targeting ligand increased cellular internalization, CAD as the pH-sensitive component triggered rapid drug release, Ce6 as the photosensitizer induced reactive oxygen species (ROS) generation, and CAT decomposed intracellular H2O2 to produce oxygen in situ. Oxygen production efficiently decreased the expression of hypoxia-inducible factor-1α (HIF-1α) and P-glycoprotein (P-gp), which enhanced chemotherapy efficiency. In addition, sufficient oxygen further amplified PDT-mediated cell-killing and apoptosis in hypoxic tumor. In vivo studies showed that combined chemo-photodynamic therapy by LCC@Ce6-NPs led to the most effective inhibition of tumor growth (TGI>90%), and even partially ablated tumor. Thus, this nano-enzyme prodrug platform can be a potentially effective treatment in clinical cancer therapy, and married to other therapeutic agents. Statement of SignificanceHypoxia in solid tumors seriously impedes the efficacy of chemotherapy or photodynamic therapy. Herein, we designed hybrid nano-enzyme prodrug particles to improve hypoxia-mediated limitations on cancer therapy. Lactobionic acid (LA) as the hydrophilic outer layer of particles increased cellular uptake by receptor-mediated endocytosis, and cis-aconitic anhydride-linked doxorubicin (CAD) as the pH sensitive component inside particles efficiently triggered DOX and Ce6 release. More importantly, catalase (CAT) as the backbone of particles was capable of greatly relieving tumor hypoxia through catalyzing the decomposition of H2O2 in situ. Oxygen re-generation not only prevented hypoxia-mediated chemo-resistance, but also amplified PDT-induced ROS cell-killing ability. As a result, the multiple combination action of this nano-system could simultaneously sensitize chemo-photodynamic therapy, thus significantly enhancing tumor therapy.

N-[18F]-Fluoroacetylcrizotinib: A potentially potent and selective PET tracer for molecular imaging of non-small cell lung cancer

N-[18F]fluoroacetylcrizotinib, a fluorine-18 labeled derivative of the first FDA approved tyrosine kinase inhibitor (TKI) for the treatment of Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC), crizotinib, was successfully synthesized for use in positron emission tomography (PET). Sequential in vitro biological evaluation of fluoracetylcrizotinib and in vivo biodistribution studies of [18F]fluoroacetylcrizotinib demonstrated that the biological activity of the parent compound remained unchanged, with potent ALK kinase inhibition and effective tumor growth inhibition. These results show that [18F]fluoroacetylcrizotinib has the potential to be a promising PET ligand for use in NSCLC imaging. The utility of PET in this context provides a non-invasive, quantifiable method to inform on the pharmacokinetics of an ALK-inhibitor such as crizotinib prior to a clinical trial, as well as during a trial in the event of acquired drug resistance.

Multifunctional Bismuth Ferrite Nanocatalysts with Optical and Magnetic Functions for Ultrasound-Enhanced Tumor Theranostics.

Ultrasound (US)-assisted oncotherapy has aroused extensive attention due to its capacities to conquer significant restrictions covering short tissue penetration depth and high phototoxicity in photoinduced therapy. We herein developed a class of pure-phase perovskite-type bimetallic oxide, namely, bismuth ferrite nanocatalysts (BFO NCs), for multimodality imaging-guided and US-enhanced chemodynamic therapy (CDT) against malignant tumors. As-prepared BFO nanoparticles with poly(ethylene glycol)-grafted phosphorylated serine (pS-PEG) modification exhibit satisfactory physiological stability and biocompatibility. The BFO NCs also present high fluorescence emission within the second near-infrared region when irradiated with an 808 nm laser. Intriguingly, the BFO NCs demonstrate highly efficient US-enhanced generation of hydroxyl free radicals, as the cavitation bubbles produced by US trigger partial grievous turbulence and promote the transfer rate of the Fenton reagents. Thus, the BFO NCs enable effective inhibition of tumor growth assisted by external US, and the treatment efficacy can be monitored by computer tomography, magnetic resonance, and fluorescence imaging. Meanwhile, H2O2 and US, as a double logic gate, activate the BFO NCs to trigger the iron-catalyzed and US-enhanced CDT with high specificity and treatment efficiency. Therefore, the BFO NCs as a theranostic agent with an enhanced chemodynamic therapeutic effect assisted by external US and a multimodality imaging capacity are put forward, which show a promising prospect for noninvasive chemodynamic oncotherapy.

Evaluation of tumor growth inhibition activity of a novel multi-TRK inhibitor ABP-1130 on glioblastoma xenograft model.

e14507 Background: Glioblastoma, also known as glioblastoma multiforme (GBM), is the most aggressive cancer that begins within the brain. Glioblastoma is a difficult to treat tumor with therapeutics limited by their ability to cross the blood brain barrier. Receptor tyrosine kinases (TRK) inhibitor is reported one of therapies for glioblastoma. ABP-1130 is a novel and potent small molecular multi-TRK Inhibitor for several prime tyrosine kinases (TRKs), such as EGFR, HER2, C-Met, and BTK with potential to treat glioblastoma. Pre-clinical studies with ABP-1130, especially study to evaluate its tumor growth inhibition effect on glioblastoma xenograft model, are planned in progress. Methods: (1) Mobility-Shift Assay used to Analyze the multi-TRK (such as EGFR, HER2, C-Met, and BTK) Inhibition activity of new anti-tumor compounds, (2) CTG Assay used to analyze the inhibition activity of LN-229 Cell Line, (3) Anti-tumor inhibition study of ABP-1130 with the brain cancer nude mice, (4) Safety studies of ABP-1130 for Ames, hERG, and MTD. Results: It was determined that its multi-TRK inhibition activity (IC50) of ABP-1130 was 7nM to EGFR, 3.6nM to HER2, 3.2nM to C-Met, and 3.7nM to BTK, respectively. Its inhibition activity for Cell Line LN-229 was 0.02 µM. In anti-tumor inhibition study with the LN-229 tumor nude mice for 28 days, the anti-tumor inhibition activity of ABP-1130 (40 mg/kg, QD) was significantly observed, and the average volume of brain tumors in nude mice (six mice/each group) was reduced from 122 mm3 to < 10mm3 (vs Pazopanib as a positive control, 50mg/kg, tumor volume increased from 123 to 867mm3). Moreover, for other safety issues, its Ames is negative and hERG is > 30 µM, and no test-article related death or adverse events occurred in maximum tolerated dose (MTD) studies with ABP-1130 (100mg/kg, QD) for 14 days. ABP-1130 also had very good metabolic stability in Human (T1/2 = 193min). Conclusions: Based on our completed preclinical study results, ABP-1130 is a novel and potent multi-TRK Inhibitor, showing excellent enzymatic activity, prominent in-vitro anti-cancer activity, and significant tumor growth inhibition activity with tolerable toxicity in glioblastoma tumor xenograft in nude mice model. It is highly warranted to continue further investigation in glioblastoma.

Functional Gadofullerene Nanoparticles Trigger Robust Cancer Immunotherapy Based on Rebuilding an Immunosuppressive Tumor Microenvironment.

Cancer immunotherapy as a novel cancer therapeutic strategy has shown enormous promise. However, the immunosuppressive tumor microenvironment (ITM) is a primary obstacle. Tumor-associated macrophages (TAMs) as a major component of immune cells in a tumor microenvironment are generally polarized to the M2 phenotype that not only accelerates tumor growth but also influences the infiltration of lymphocytes and leads to immunosuppression. Thus, rebuilding ITM by re-educating TAMs and increasing infiltration of lymphocytes is a promising strategy. Herein, gadofullerene (GF-Ala) nanoparticles are demonstrated to reprogram TAMs to M1-like and increase the infiltration of cytotoxic T lymphocytes (CTLs), achieving effective inhibition of tumor growth. Notably, the modulation of ITM by GF-Ala promotes the anticancer efficacy of anti-PD-L1 immune checkpoint inhibitor, achieving superior synergistic treatment. Additionally, GF-Ala nanoparticles can be mostly excreted from the body and cause no obvious toxicity. Together, this study provides an effective immunomodulation strategy using gadofullerene nanoparticles by rebuilding ITM and synergizing immune checkpoint blockade therapy.

Ultrasound-Activated Cascade Effect for Synergistic Orthotopic Pancreatic Cancer Therapy.

SummaryIn some malignant tumor, especially for pancreatic tumor, poor solid-tumor penetration of nanotherapeutics impedes their treatment efficacy. Herein, we develop a polymer-peptide conjugate with the deep tissue penetration ability, which undergoes a cascade process under ultrasound (US), including (1) the singlet oxygen 1O2 is generated by P18, (2) the thioketal bond is cleaved by the 1O2, (3) the departure of PEG chains leads to the in situ self-assembly, and (4) the resultant self-assembled PK nanoparticles show considerable cellular internalization. Owing to the synergistic effect of US on increasing the membrane permeability, the endocytosis and lysosome escape of PK nanoparticles are further enhanced effectively, resulting in the improved therapeutic efficacy. Thanks to the high tissue-penetrating depth and spatial precision of US, PTPK presents enhanced tumor inhibition in an orthotopic pancreatic tumor model. Therefore, the US-activated cascade effect offers a novel perspective for precision medicine and disease theranostics.

OR03-01 Effects Of Alpha-emitting Meta-211At-astato-benzylguanidine (211At-MABG) Compared To 131I-meta-iodobenzylguanidine (131I-MIBG) on Tumor Growth Suppression in a Pheochromocytoma Mouse Model

Objectives: Given the limited treatment approaches currently available for patients with metastatic pheochromocytoma and paraganglioma (PPGL), new effective approaches are being sought. The radioisotope approach using 131I-meta-iodobenzylguanidine (131I-MIBG) has limited survival benefits in metastatic PPGL but is currently considered one of the standard therapeutic approaches. In theory, the alpha-emitting radiopharmaceutical meta-211At-astato-benzylguanidine (211At-MABG) could be a very effective targeted treatment for metastatic PPGL. However, this possibility has not been evaluated. Therefore, the purpose of this study was to evaluate the tumor growth suppression effects of 211At-MABG compared to 131I-MIBG using a PC-12 mouse pheochromocytoma model. Methods: Rat pheochromocytoma (PC-12) cells were subcutaneously inoculated into male BALB/c nu/nu nude mice. When tumor volumes reached approximately 300 mm3, mice bearing PC-12 tumors received intravenously either 1.11 MBq of 211At-MABG (n=6), 31 MBq of 131I-MIBG (n=3) or vehicle solvent (n = 6). The tumor volume was measured 3 times per week for 2 weeks. The tumor volume was compared among the three groups. Results: At 14 days, the tumor volumes significantly increased in the control group (328.82±83.65 to 3568.83±693.23 mm3, P<0.001). In contrast, there were no significant changes in tumor volumes in the 211At-MABG group (284.65±56.77 to 274.3±87.95 mm3, P=0.616) and 131I-MIBG group (484.40±46.25 to 323.93±127.27 mm3, P=0.084). The 211At-MABG group showed significantly lower percentage change in tumor volume than did the control group (-5.0±15.99 vs. 1043.83±320.79%, P<0.001), and 131I-MIBG group also showed significant volume reduction rate compared to that of the control group (-34.33±21.39 vs. 1043.82±320.79%, P<0.001). There was no significant difference in percentage tumor volume changes between the 211At-MABG and 131I-MIBG groups (P=0.052). Conclusion: At 14 days after radiopharmaceutical administration, 211At-MABG produced significant tumor volume reduction as compared to that in the control group and to that associated with 131I-MIBG, which is considered one of the current treatment options. Therefore, 211At-MABG may have future clinical applications for the treatment of metastatic pheochromocytoma and paraganglioma.

Ultrasound-Enhanced Chemo-Photodynamic Combination Therapy by Using Albumin "Nanoglue"-Based Nanotheranostics.

The combination of photodynamic therapy (PDT) and chemotherapy is considered to enhance the antitumor immunity and combat multidrug resistance. Some preclinical studies have reported a positive therapeutic outcome of using ultrasound (US) irradiation to enhance chemotherapy, but the combination of these three modalities has yet to be investigated. On the basis of the discovery of a strong affinity between a photosensitizer sinoporphyrin sodium (DVDMS) and human serum albumin (HSA), a clinically used albumin-paclitaxel (HSA-PTX) nanoparticle is utilized as a "nanoglue" to load a large amount of DVDMS by simple mixing. The five conformations of HSA and DVDMS with highest affinity were calculated using AutoDock Vina. The obtained albumin "nanoglue"-based nanotheranostics, HSA-PTX-DVDMS (HPD), has better fluorescence imaging and PDT performance than free DVDMS, probably due to the reduced quenching of DVDMS after dispersion in albumin. An efficacious tumor-targeting enhancement of chemotherapy by US irradiation is verified in a bilateral subcutaneous 4T1 tumors model. With the aid of US irradiation, the combined PDT and chemotherapy mediated by HPD achieve effective tumor growth inhibition. Overall, this "nanoglue"-based nanotheranostics is composed of several clinically used elements and integrates three clinical modalities with application prospects in clinic.

Targeted alpha therapy using astatine (211At)-labeled phenylalanine: A preclinical study in glioma bearing mice.

Phenylalanine derivatives, which target tumors especially through L-type amino acid transporter-1 (LAT1), have elicited considerable attention. In this study, we evaluated the treatment effect of phenylalanine labeled with the alpha emitter astatine (211At-PA) in tumor bearing mice. The C6 glioma, U-87MG, and GL261 cell lines were subjected to a cellular 211At-PA uptake analysis that included an evaluation of the uptake inhibition by the system L amino acid transporter inhibitor 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH). BCH significantly inhibited para-211At-PA uptake in C6 glioma (12.2 ± 0.8%), U-87MG (27.6 ± 1.1%), and GL261 (12.6 ± 2.0%) cells compared to baseline, suggesting an uptake contribution by system L amino acid transporters. Subsequently, xenograft and allograft models were prepared by subcutaneously injecting C6 glioma (n = 12) or GL-261 cells (n = 12), respectively. C6 glioma mice received three 211At-PA doses (0.1, 0.5, or 1 MBq, n = 3/dose), while GL261 mice received one high dose (1 MBq, n = 7). 211At-PA exhibited a tumor growth suppression effect in C6 glioma models in a dose-dependent manner as well as in GL-261 models. This phenylalanine derivative labeled with astatine may be applicable as an alpha therapy that specifically targets system L amino acid transporters.

Reshaping Tumor Immune Microenvironment through Acidity-Responsive Nanoparticles Featured with CRISPR/Cas9-Mediated Programmed Death-Ligand 1 Attenuation and Chemotherapeutics-Induced Immunogenic Cell Death.

Blocking immune checkpoints with monoclonal antibody has been verified to achieve potential clinical successes for cancer immunotherapy. However, its application has been impeded by the "cold" tumor microenvironment. Here, weak acidity-responsive nanoparticles co-loaded with CRISPR/Cas9 and paclitaxel (PTX) with the ability to convert "cold" tumor into "hot" tumor are reported. The nanoparticles exhibited high cargo packaging capacity, superior transfection efficiency, well biocompatibility, and effective tumor accumulation. The CRISPR/Cas9 encapsulated in nanoparticles could specifically knock out cyclin-dependent kinase 5 gene to significantly attenuate the expression of programmed death-ligand 1 on tumor cells. More importantly, PTX co-delivered in nanoparticles could significantly induce immunogenic cell death, reduce regulatory T lymphocytes, repolarize tumor-associated macrophages, and enhance antitumor immunity. Therefore, the nanoparticles could effectively convert cold tumor into hot tumor, achieve effective tumor growth inhibition, and prolong overall survival from 16 to 36 days. This research provided a referable strategy for the development of combinatorial immunotherapy and chemotherapy.

Anti-angiogenic effect of a chemically sulfated polysaccharide from Phellinus ribis by inhibiting VEGF/VEGFR pathway

Previous studies have demonstrated that the sulfated polysaccharide named PRP-S16 could inhibit the proliferation, migration, and tube formation of endothelial cells in vitro. Here, its anti-angiogenic effect and mechanism in vivo were investigated by Lewis lung carcinoma (LLC) mice model. PRP-S16 significantly reduced the microvessel density (MVD) of tumor, exhibiting a high tumor growth inhibitory effect in LLC mice. All designed assays including quantitative real-time PCR, immunohistochemistry, enzyme-linked immunosorbent assay and western blotting showed that PRP-S16 reduced the mRNA and the protein expression of vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2) in serum or tumor tissue of mice. Western blotting also detected decreased phosphorylated (p)-VEGFR-1, p-VEGFR-2, hypoxia-inducible factor-1α (HIF-1α), protein kinase B (Akt), and matrix metalloproteinases-9 (MMP-9). PRP-S16 had no adverse effects on angiogenesis in non-target organs. These findings suggested that the mechanism of anti-angiogenesis of PRP-S16 in vivo was due to inhibition of VEGF/VEGFR signaling pathway and it might be a promising candidate for tumor by anti-angiogenic therapy.

Astragalus membranaceus-Derived Anti-Programmed Death-1 Monoclonal Antibodies with Immunomodulatory Therapeutic Effects against Tumors.

Astragalus membranaceus polysaccharide (APS) components are main ingredients of TCM and have proven efficacy to activate T cells and B cells, enhancing immunity in humans. In this study, elevated cytokine and anti-PD-1 antibody titers were found in mice after immunization with APS. Therefore, phage-display technology was utilized to isolate specific anti-programmed death-1 (PD-1) antibodies from mice stimulated by APS and to confirm whether the isolated anti-PD-1 antibody could inhibit the interaction of PD-1 with the programmed death-ligand 1 (PD-L1), resulting in tumor growth inhibition. The isolated single-chain fragment variable (scFv) S12 exhibited the highest binding affinity of 20 nM to PD-1, completed the interaction between PD-1 and PD-L1, and blocked the effect of PD-L1-induced T cell exhaustion in peripheral blood mononuclear cells in vitro. In the animal model, the tumor growth inhibition effect after scFv S12 treatment was approximately 48%. However, meaningful synergistic effects were not observed when scFv S12 was used as a cotreatment with ixabepilone. Moreover, this treatment caused a reduction in the number of tumor-associated macrophages in the tumor tissue. These experimental results indirectly indicate the ability of APS to induce specific antibodies associated with the immune checkpoint system and the potential benefits for improving immunity in humans.

Polyethylenimine Nanogels Incorporated with Ultrasmall Iron Oxide Nanoparticles and Doxorubicin for MR Imaging-Guided Chemotherapy of Tumors.

Development of versatile nanoplatforms for cancer theranostics remains a hot topic in the area of nanomedicine. We report here a general approach to create polyethylenimine (PEI)-based hybrid nanogels (NGs) incorporated with ultrasmall iron oxide (Fe3O4) nanoparticles (NPs) and doxorubicin for T1-weighted MR imaging-guided chemotherapy of tumors. In this study, PEI NGs were first prepared using an inverse emulsion approach along with Michael addition reaction to cross-link the NGs, modified with citric acid-stabilized ultrasmall Fe3O4 NPs through 1-ethyl-3-(3-(dimethylamino)propyl) carbodiimide hydrochloride (EDC) coupling, and physically loaded with anticancer drug doxorubicin (DOX). The formed hybrid NGs possess good water dispersibility and colloidal stability, excellent DOX loading efficiency (51.4%), pH-dependent release profile of DOX with an accelerated release rate under acidic pH, and much higher r1 relaxivity (2.29 mM-1 s-1) than free ultrasmall Fe3O4 NPs (1.15 mM-1 s-1). In addition, in contrast to the drug-free NGs that possess good cytocompatibility, the DOX-loaded hybrid NGs display appreciable therapeutic activity and can be taken up by cancer cells in vitro. With these properties, the developed hybrid NGs enabled effective inhibition of tumor growth under the guidance of T1-weighted MR imaging. The developed hybrid NGs may be applied as a versatile nanoplatform for MR imaging-guided chemotherapy of tumors.

Synthesis and structure-activity relationship study of water-soluble carbazole sulfonamide derivatives as new anticancer agents

Here, we formulated and investigated the structure-activity relationships of novel N-substituted carbazole sulfonamide derivatives with improved physicochemical properties. Most of these new compounds displayed good aqueous solubility. Certain molecules presented strong in vitro antiproliferative and in vivo antitumor activity. Relative to the control, 50 mg/kg compound 3v substantially reduced human HepG2 xenograft mouse tumor growth by 54.5% and its efficacy was comparable to that of CA-4P. Compound 3h demonstrated anticancer efficacy in both subcutaneous and orthotopic HepG2 xenograft mouse models. We also developed a novel synthetic method for 7-hydroxy-substituted carbazole sulfonamides. Compared with the control, 25 mg/kg compound 4c inhibited human HepG2 xenograft mouse tumor growth by 71.7% and was more potent than 50 mg/kg CA-4P with only 50% tumor shrinkage efficacy. Among the three water-soluble carbazole sulfonamide derivatives formulated in the present study, compound 4c displayed the most effective tumor growth inhibition in vivo and merit further investigation as potential antitumor agents for cancer therapy.

Sequential delivery of nanoformulated α-mangostin and triptolide overcomes permeation obstacles and improves therapeutic effects in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease exhibiting the poorest prognosis among solid tumors. The efficacy of conventional therapies has been hindered largely due to the insufficient chemotherapeutic delivery to the dense desmoplastic tumor stroma, and the extremely high or toxic dose needed for chemotherapy. Traditional Chinese Medicine (TCM) contains effective components that can effectively regulate tumor microenvironment and kill tumor cells, providing promising alternatives to PDAC chemotherapy. In this study, two active drug monomers of TCM were screened out and a sequentially targeting delivery regimen was developed to realize the optimized combinational therapy. Transforming growth factor-β (TGF-β) plays an indispensable role in promoting cancer-associated fibroblasts (CAFs) activation and proliferation, and CAFs have caused major physical barriers for chemotherapeutic drug delivery. Herein, CAFs-targeting biodegradable polymer nanoparticle (CRE-NP(α-M)) coated with CREKA peptide and loaded with TCM α-mangostin (α-M) was developed to modulate tumor microenvironment by interfering of TGF-β/Smad signaling pathway. Low pH-triggered micelle modified with CRPPR peptide and loaded with another TCM triptolide was constructed to increase the therapeutic effect of triptolide at the tumor sites and reduced its damage to main organs. As expected, CRE-NP(α-M) effectively inactived CAFs, reduced extracellular matrix production, promoted tumor vascular normalization and enhanced blood perfusion at the tumor site. The sequentially targeting drug delivery regimen, CRP-MC(Trip) following CRE-NP(α-M) pretreatment, exhibited strong tumor growth inhibition effect in the orthotopic tumor model. Hence, sequentially targeting delivery of nanoformulated TCM offers an efficient approach to overcome the permeation obstacles and improve the effect of chemotherapy on PDAC, and provides a novel option to treat desmoplastic tumors.

Dual-response oxygen-generating MnO2 nanoparticles with polydopamine modification for combined photothermal-photodynamic therapy

Photonic therapy (e.g., photodynamic therapy (PDT) and photothermal therapy (PTT)), features easy handling, good targeting, high curative effect and lower side effects compared to other treatments, thus showing considerable potential in cancer treatment. However, adverse tumor microenvironment, low light conversion efficiency, and inherent toxicity of photonic agents limit their further application in clinic. In this work, hollow mesoporous MnO2 nanoparticles (NPs) loaded with photosensitizer chlorin e6 and coated with folic acid-functionalized polydopamine were fabricated, and used as a platform for photonic therapy. The NPs enabled accurately controlled drug release, and sustainable and extensive O2 production by reacting with endogenous H2O2 in vitro. In addition, the NPs allowed efficient NIR light-to-heat conversion, owing to the core-shell MnO2/polydopamine structure. With the synergy of folic acid mediated active targeting and enhanced permeability and retention effect mediated passive targeting, a pronounced NPs accumulation at the tumor sites of mouse model was observed. The NPs also exhibited excellent biodegradation properties, alleviating the possible concerns about the long-term safety of photonic agents. Finally, a combination of O2-strengthened PDT and PTT resulted in effective tumor growth inhibition upon irradiation with 660 nm and 808 nm laser in vivo treatment. The above features of the devised NPs highlight their potential for improved cancer therapy and imaging.

Camouflaging Nanoparticles with Brain Metastatic Tumor Cell Membranes: A New Strategy to Traverse Blood–Brain Barrier for Imaging and Therapy of Brain Tumors

AbstractGlioblastoma multiforme is one of the most fatal intracranial tumors with no effective treatment. The drug concentration in tumor sites is usually insufficient to reach therapeutic levels, due to poor blood–brain‐barrier (BBB) permeability and short biological half‐life. Inspired by the proneness of those malignant tumors to brain metastasis, a brain metastatic tumor cell membrane‐coated nanocarrier with core–shell structure is constructed to cross BBB for imaging and photothermal therapy of early brain tumors. The cell membranes as the shell are extracted from different metastatic tumor cells, which endow the nanoparticles with BBB‐crossing ability and long circulation. Indocyanine green (ICG)‐loaded polymeric nanoparticle as the core allows fluorescence imaging and phototherapy of brain tumors. The as‐prepared biomimetic nanoparticles display superb BBB penetration and effective suppression of tumor growth. These findings suggest the biomimetic nanotechnology provides a new insight for the design of BBB‐crossing nanomaterials and is promising to treat brain diseases.

Abstract P3-11-19: Preclinical model of TNBC: Dasatinib attenuates Src pathway signaling and combined with veliparib and carboplatin potently inhibits tumor growth

Abstract Background: The combination of a poly ADP ribose polymerase (PARP) inhibitor with a DNA-damaging agent has shown promise in treating triple-negative breast cancer (TNBC); however, not all patients respond to this combination. The Src protein kinase modulates multiple cancer cell properties and plays a key role in tumorigenic processes. However, Src inhibitors as single agents have shown limited effects in solid tumors. In this study, we examined the antitumor effects of the Src inhibitor dasatinib, the PARP inhibitor veliparib, and the DNA-damaging agent carboplatin in TNBC cells in vitro and tumors in vivo to try to identify the combination with the most clinical potential. Methods: The BRCA-mutated and PTEN null TNBC cell line, SUM149PT, was used in this study. For in vitro studies, proliferation, cellular apoptosis, and 3D on-top clonogenic growth were measured, tube formation assays and western blot analysis were performed. For in vivo studies, a xenograft model was used to examine treatment responses, and immunohistochemical analysis was performed. Results: Surprisingly, treatment with the combination of veliparib plus carboplatin led to an increase in Src phosphorylation. Importantly, addition of dasatinib attenuated Src overexpression induced by veliparib plus carboplatin and further inhibited the downstream signaling of Src, thereby enhancing the antitumor efficacy of veliparib plus carboplatin. In an SUM149PT xenograft model, the triple combination of dasatinib with veliparib plus carboplatin showed greater tumor growth inhibitory effects compared with single agents or double combinations. No systemic toxicity was observed in mice treated with the triple combination. Conclusion: Here, we provide novel evidence that veliparib combined with carboplatin drives Src activation in the preclinical model tested. Moreover, we provide provocative in vitro and in vivo data highlighting the potential for increasing therapeutic efficacy by combining dasatinib with veliparib and carboplatin in BRCA-mutated and PTEN null TNBC. Citation Format: yuliang Sun, Xiaoqian Lin, Jennifer Aske, Casey Williams, Mark Abramovitz, Brian Leyland-Jones. Preclinical model of TNBC: Dasatinib attenuates Src pathway signaling and combined with veliparib and carboplatin potently inhibits tumor growth [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-11-19.