Nanoarchitectured conjugates targeting angiogenesis: investigating heparin-taurocholate acid conjugates (LHT7) as an advanced anti-angiogenic therapy for brain tumor treatment.

BACKGROUND: Glioblastoma is a highly malignant brain tumor associated with poor prognosis. Conventional therapeutic approaches have limitations due to their toxic effects on normal tissue and the development of tumor cell resistance. This study aimed to explore alternative mechanisms for glioblastoma treatment by targeting angiogenesis. METHODS: The study investigated the anti-angiogenic properties of heparin in glioblastoma treatment. To overcome the limitations of heparin, a heparin-taurocholate conjugate (LHT7) was synthesized by conjugating heparin to taurocholic acid. The study utilized the U87MG human glioblastoma cell line and human umbilical vein endothelial cells (HUVEC) as experimental models. Cell viability assays and sprouting assays were performed to assess the effects of LHT7. Additionally, phosphorylation of angiogenesis-related proteins, such as phospho-ERK and phospho-VEGFR2, was measured. The anti-angiogenic effects of LHT7 were further evaluated using a glioblastoma orthotopic mouse model. RESULTS: Treatment with LHT7 resulted in a dose-dependent reduction in cell viability in U87MG human glioblastoma cells. The sprouting of HUVEC cells was significantly decreased upon LHT7 treatment. Furthermore, LHT7 treatment led to a decrease in the phosphorylation of angiogenesis-related proteins, including phospho-ERK and phospho-VEGFR2. In the glioblastoma orthotopic mouse model, LHT7 exhibited anti-angiogenic effects, supporting its potential as a therapeutic agent. CONCLUSIONS: The conjugation of heparin and taurocholic acid to create LHT7 offers several advantages over conventional therapeutic approaches for glioblastoma. LHT7 demonstrated anti-angiogenic properties, as evidenced by the reduction in cell viability and inhibition of endothelial cell sprouting. Moreover, LHT7 modulated the phosphorylation of angiogenesis-related proteins. These findings suggest that LHT7 holds promise as a medication for glioblastoma treatment, offering potential implications for improving patient outcomes.

Gastrointestinally absorbable lactoferrin-heparin conjugate with anti-angiogenic activity for treatment of brain tumor.

Glioblastoma multiforme (GBM) is a central nervous system disease with poor prognosis. Curative treatments for GBM involve chemotherapy, radiotherapy, and surgical pathways. Recently, antiangiogenic therapy through medications has been tried to slow tumor growth, but the drugs can induce side effects. To overcome these limitations, we developed a new orally absorbable form of heparin that can attenuate angiogenic activity by binding to growth factors around the tumor tissue. We conjugated lactoferrin (Lf) to heparin because Lf can be orally absorbed, and it interacts with the lactoferrin receptor (Lf-R) expressed on the intestine, blood-brain barrier (BBB), and glioma tumor masses. We successfully conjugated Lf and heparin by amide bond formation, as evidenced by advanced physicochemical properties such as pharmacokinetics and stability in acidic condition. This new material inhibited angiogenesis in vitro without toxicity. In addition, Lf-heparin administered orally to GBM orthotopic mice was absorbed in the small intestine and delivered specifically to the brain tumor by receptor transcytosis (Lf-R). Lf-heparin further attenuated angiogenesis progression in GBM orthotopic mice. Based on these results, Lf-heparin shows potential as a new oral medication for treatment of glioblastoma.

Anticancer Effect of Heparin-Taurocholate Conjugate on Orthotopically Induced Exocrine and Endocrine Pancreatic Cancer.

Pancreatic cancers are classified based on where they occur, and are grouped into those derived from exocrine and those derived from neuroendocrine tumors, thereby experiencing different anticancer effects under medication. Therefore, it is necessary to develop anticancer drugs that can inhibit both types. To this end, we developed a heparin-taurocholate conjugate, i.e., LHT, to suppress tumor growth via its antiangiogenic activity. Here, we conducted a study to determine the anticancer efficacy of LHT on pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumor (PNET), in an orthotopic animal model. LHT reduced not only proliferation of cancer cells, but also attenuated the production of VEGF through ERK dephosphorylation. LHT effectively reduced the migration, invasion and tube formation of endothelial cells via dephosphorylation of VEGFR, ERK1/2, and FAK protein. Especially, these effects of LHT were much stronger on PNET (RINm cells) than PDAC (PANC1 and MIA PaCa-2 cells). Eventually, LHT reduced ~50% of the tumor weights and tumor volumes of all three cancer cells in the orthotopic model, via antiproliferation of cancer cells and antiangiogenesis of endothelial cells. Interestingly, LHT had a more dominant effect in the PNET-induced tumor model than in PDAC in vivo. Collectively, these findings demonstrated that LHT could be a potential antipancreatic cancer medication, regardless of pancreatic cancer types.

Protein-Based Drug Delivery in Brain Tumor Therapy.

Despite the use of active surgeries, radiotherapy, and chemotherapy in clinical practice, brain tumors are still a difficult health problem due to their rapid development and poor prognosis. To treat brain tumors, various nanoparticles can be used to target effective physiological conditions based on continuously changing vascular characteristics and microenvironments to promote effective brain tumor-targeting drug delivery. In addition, a brain tumor-targeting drug delivery system that increases drug accumulation in the brain tumor area and reduces toxicity in the normal brain and peripheral tissues is needed. However, the blood-brain barrier ​​is a big obstacle for drug delivery to the brain. In this chapter, we provide a broad overview of brain drug delivery and current strategies over the last few years. In addition, several questions have been reconsidered, such as whether nanoparticles believed to be delivered to the brain can pass through the blood-brain barrier, whether the drug is delivered to the target site, and what brain tumor treatment is possible.

Inducing angiogenesis with the controlled release of nitric oxide from biodegradable and biocompatible copolymeric nanoparticles.

PURPOSE: Nitric oxide (NO) can be clinically applied at low concentrations to regulate angiogenesis. However, studies using small molecule NO donors (N-diazeniumdiolate, S-nitrosothiol, etc) have yet to meet clinical requirements due to the short half-life and initial burst-release profile of NO donors. In this study, we report the feasibility of methoxy poly(ethylene glycol)-b-poly(lactic-co-glycolic acid) (mPEG-PLGA) nanoparticles (NPs) as NO-releasing polymers (NO-NPs) for inducing angiogenesis. MATERIALS AND METHODS: The mPEG-PLGA copolymers were synthesized by typical ring-opening polymerization of lactide, glycolide and mPEG as macroinitiators. Double emulsion methods were used to prepare mPEG-PLGA NPs incorporating hydrophilic NONOate (dieth-ylenetriamine NONOate). RESULTS: This liposomal NP encapsulates hydrophilic diethylenetriamine NONOate (70%±4%) more effectively than other previously reported materials. The application of NO-NPs at different ratios resulted in varying NO-release profiles with no significant cytotoxicity in various cell types: normal cells (fibroblasts, human umbilical vein endothelial cells and epithelial cells) and cancer cells (C6, A549 and MCF-7). The angiogenic potential of NO-NPs was confirmed in vitro by tube formation and ex vivo through an aorta ring assay. Tubular formation increased 189.8% in NO-NP-treated groups compared with that in the control group. Rat aorta exhibited robust sprouting angiogenesis in response to NO-NPs, indicating that NO was produced by polymeric NPs in a sustained manner. CONCLUSION: These findings provide initial results for an angiogenesis-related drug development platform by a straightforward method with biocompatible polymers.