Angiopep-2-modified calcium arsenite-loaded liposomes for targeted and pH-responsive delivery for anti-glioma therapy.

The blood-brain barrier (BBB) is the most critical obstacle in the treatment of central nervous system disorders, such as glioma, the most typical type of brain tumor. To overcome the BBB and enhance drug-penetration abilities, we used angiopep-2-modified liposomes to deliver arsenic trioxide (ATO) across the BBB, targeting the glioma. Angiopep-2-modified calcium arsenite-loaded liposomes (A2-PEG-LP@CaAs), with uniformly distributed hydrodynamic diameter (96.75 ± 0.57 nm), were prepared using the acetate gradient method with high drug-loading capacity (7.13 ± 0.72%) and entrapment efficiency (54.30 ± 9.81%). In the acid tumor microenvironment, arsenic was responsively released, thereby exerting an anti-glioma effect. The anti-glioma effect of A2-PEG-LP@CaAs was investigated both in vitro and in vivo. As a result, A2-PEG-LP@CaAs exhibited a potent, targeted anti-glioma effect mediated by the lipoprotein receptor-related (LRP) receptor, which is overexpressed in both the BBB and glioma. Therefore, A2-PEG-LP@CaAs could dramatically promote the anti-glioma effect of ATO, as a promising strategy for glioma therapy.

Zeolitic Imidazolate Framework-8 as pH-Sensitive Nanocarrier for "Arsenic Trioxide" Drug Delivery.

Previous results revealed that arsenic trioxide might be used as promising therapeutic agent for the treatment of some solid tumours as atypical teratoid rhabdoid tumours (ATRT). However, in order to become an approved drug for solid tumour treatment, the active formulation has to get more efficient and feasible-but at the same time less toxic. One of the possibilities to achieve this dichotomy is to use nanomedicine tools. Herein, we report on the Zn-based metal-organic framework ZIF-8 (Zeolitic Imidazolate Framework-8) which turned out to be a promising candidate for the delivery of AsIII species. It conjointly features a high drug loading capacity and a prominent pH-triggered release behaviour. AsIII -loaded ZIF-8 nanoparticles coated and non-coated with polyethylene glycol were studied by XRPD, IR, Raman, TGA, TEM, EDX, CHN-elemental analysis, sorption analysis and ICP-OES, and their cytotoxicity was evaluated in vitro.

Arsenic trioxide-eluting electrospun nanofiber-covered self-expandable metallic stent reduces granulation tissue hyperplasia in rabbit trachea.

Stent-related granulation tissue hyperplasia is a major complication that limits the application of stents in airways. In this study, an arsenic trioxide-eluting electrospun nanofiber-covered self-expandable metallic stent (ATO-NFCS) was developed. Poly-L-lactide-caprolactone (PLCL) was selected as the drug-carrying polymer. Stents with two different ATO contents (0.4% ATO/PLCL and 1.2% ATO/PLCL) were fabricated. The in vitro release in simulated airway fluid suggested that the total ATO release time was 1 d. The growth of human embryonic pulmonary fibroblasts (CCC-HPF-1), normal human bronchial epithelial cells and airway smooth muscle cells was inhibited by ATO. When embedded in paravertebral muscle, the nanofiber membrane showed good short-term and long-term biological effects. In an animal study, placement of the ATO-NFCS in the trachea through a delivery system under fluoroscopy was feasible. The changes in liver and kidney function 1 and 7 d after ATO-NFCS placement were within the normal range. On pathological examination, the heart, liver, spleen, lungs and kidneys were normal. The effectiveness of the ATO-NFCS in reducing granulation tissue hyperplasia and collagen deposition was demonstrated in the rabbit airway (n = 18) at 4 weeks. The present study preliminarily investigated the efficacy of the ATO-NFCS in reducing granulation tissue formation in the trachea of rabbits. The results suggest that the ATO-NFCS is safe in vivo, easy to place, and effective for the suppression of granulation tissue formation.

Construction of arsenic-metal complexes loaded nanodrugs for solid tumor therapy: A mini review.

Arsenic trioxide (As2O3), a front-line therapeutic agent against acute promyelocytic leukemia, has a broad spectrum against malignancies. Unfortunately, the clinical application of As2O3 in treating hematological cancers has not been transformed to solid tumors, for its dose-limited toxicity and undesirable pharmacokinetics. The ordinary As2O3 loaded nanodrugs (such as liposomes, polymer micelles, albumin-based nanodrugs, and silica-based nanodrugs, etc.) still could not fuel up pharmaceuticals and eradicate toxicity for low delivery efficiency caused by the instability and severe drug leakage of formulations during circulation. Recently, the approach of forming and delivering arsenic-metal complexes which will dissociate in the tumoral environment caught our mind. This is the most effective strategy to reduce drug leakage in circulation and accumulate arsenite ions in tumor sites, therefore promote the anti-tumor effect and lighten the toxicity of the drug. This review aims to explain the formation mechanism of arsenic-metal nanocomposites and summarize the constructing strategies of the arsenic-metal nanocomplexes (arsenic-nickel, arsenic-manganese, arsenic-platinum, arsenic-gadolinium, arsenic-zinc, and arsenic-iron nanobins) loaded nanodrugs for solid tumor therapy. Furthermore, the expectations and challenges of arsenic-metal complexes containing nanodrugs for cancer therapy in the future were discussed.

Dual oligopeptides modification mediates arsenic trioxide containing nanoparticles to eliminate primitive chronic myeloid leukemia cells inside bone marrow niches.

Chronic myeloid leukemia (CML) is one type of hematopoietic stem cell diseases. Although BCR-ABL1 tyrosine kinase inhibitors are remarkably effective in inducing remission in chronic phase patients, they are not curative in a majority of patients due to their failure to eradicate residual CML stem/progenitor cells, which reside in bone marrow niches. Here, we presented novel dual oligopeptides-conjugated nanoparticles and demonstrated their effective delivery of arsenic trioxide in bone marrow niches for the elimination of primitive CML cells. We encapsulated As-Ni transitional metal compounds into polymeric nanoparticles based on the reverse micelle rationale. The loading density and stability of arsenic trioxide in nanoparticles were improved. In vitro experiments demonstrated that dual oligopeptides conjugated nanoparticles could deliver arsenic trioxide into bone marrow niches including endosteal niches and vascular niches. The colony-forming activity of CML cells was remarkably restrained in the presence of metaphyseal bone fragments pre-incubated with bone marrow niche targeted arsenic nanoparticles. The in vitro vascular niche model suggested that CML cell proliferation was also successfully inhibited through a tight contact with HUVECs, which were pre-treated using niche-targeted arsenic nanoparticles. This bone marrow niche targeted delivery strategy has a potential usage for the treatment of CML and other malignant hematologic disorders originated from the bone marrow.

In vitro stability of arsenic trioxide-liposome encapsulates for acute promyelocytic leukemia treatment.

In this work, we investigated the stability of arsenic trioxide (ATO) used in leukemia treatment, encapsulated with nanoliposome, with the aid of ultrasound treatment. Stability studies of As species were followed by liquid chromatography-inductively coupled plasma mass spectrometry (LC-ICP-MS), allowing for the detection of the conversion of low amounts of As(III) to As(V) or the formation of other As species. The influence of storage temperature and time on ATO was evaluated. Low amounts of As(III) to As(V) conversions were observed when the As encapsulated with nanoliposome was incubated at 25 °C and 40 °C. However, As(III) was stable if the solution was maintained at 5 °C, even after 90 days. No formation of other As species was observed, indicating good stability of the encapsulated ATO. Next step of the work will focus on spray drying of ATO nanoliposomes-encapsuleted with the aim of long term stability of As.

Surface-modified PLGA nanoparticles with PEG/LA-chitosan for targeted delivery of arsenic trioxide for liver cancer treatment: Inhibition effects enhanced and side effects reduced.

Arsenic trioxide (As2O3), an effective drug for leukemia, is limited to be used for solid tumor treatment due to its high side effects. In this study, polyethylene glycol (PEG) and lactobionic acid (LA) modified chitosan (PLC) was synthesized and was used to coat poly(lactide-co-glycolide) (PLGA) nanoparticles for encapsulation and targeted release of As2O3 in liver cancer treatment. The As2O3-loaded PLGA/PLC nanoparticles (As2O3-PLGA/PLC NPs) were fabricated through double emulsion-solvent evaporation method and were optimized by orthogonal tests. As2O3-PLGA/PLC NPs presented suitable physical stability, positive charge, high encapsulation efficiency and drug loading, and good biocompatibility. As expected, the NPs can quickly release enough dose of As2O3 in a short time and then sustain the drug concentration. The As2O3-PLGA/PLC NPs showed effective inhibition of SMMC-7721 cells while having lower cytotoxicity against normal human liver cells (LO2 cells). Furthermore, In vivo study showed that the NPs did not present toxic effects on kidney and liver, but showed relatively high growth inhibition effect on liver tumor. Therefore, this PLGA/PLC NPs could be an effective and safe drug delivery system for liver cancer chemotherapy.

Investigation of HSA as a biocompatible coating material for arsenic trioxide nanoparticles.

The anticancer properties of arsenic trioxide (As2O3) are accompanied by highly cytotoxic effects on normal cells. This necessitates developing modalities towards the targeted delivery of As2O3. Albumins, on account of their large structure and presence of several interacting groups, are ideal for encapsulating or carrying various drugs. In the present study, human serum albumin (HSA) was chosen as a coating agent to increase the biocompatibility of As2O3. An in situ chemical precipitation method was adopted for the synthesis of HSA-coated As2O3 nanoparticles (HSA-As2O3NPs) that were further characterized by Fourier-transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), ultraviolet-visible (UV-vis) spectroscopy, inductively coupled plasma atomic emission spectrometry (ICP-AES), zeta potential and transmission electron microscopy (TEM). HSA-As2O3NPs were assessed for their biocompatibility using mouse fibroblast cells (NIH-3T3) and human dermal fibroblast (HDF) cells by a time- and dose-dependent cytocompatibility MTT assay. The safety of the HSA-As2O3 nanoparticles was assessed using haemolysis and blood cell aggregation studies. Molecular simulation studies provided evidence of interaction between HSA and As2O3. Herein, we report the development of a protein-based delivery system for As2O3 with improved biocompatibility.

Effects of surface modification of As2O3-loaded PLGA nanoparticles on its anti-liver cancer ability: An in vitro and in vivo study.

As2O3-loaded nanoparticles (NPs) based on poly (lactic-co-glycolic acid) (PLGA) were prepared by double emulsion-solvent evaporation method. Then Lactose acid (LA) and/or PEG were modified onto the NPs by chemical covalent coupling through -NH2 and -COOH. The FTIR results showed that LA and PEG could be successfully modified onto the surface of the NPs. All the As2O3-loaded PLGA NPs (As2O3@PLGA NPs) presented suitable physical stability, favorable size, and spherical shape. The in vitro release rate of As2O3 from the NPs depended on the surface of the NPs. As expected, the As2O3@PLGA-PEG/LA NPs showed a moderate release rate, the highest anticancer effects and cellular internalization against SMMC-7721 cell line. The PLGA-PEG/LA NPs could represent an effective nano-size delivery system of As2O3 for treatment of liver cancer.