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Pyrazolo[3,4-d]pyrimidine derivatives 1-5, active as c-Src inhibitors, have been selected to be formulated as drug-loaded human serum albumin (HSA) nanoparticles, with the aim of improving their solubility and pharmacokinetic properties. The present study includes the optimization of a desolvation method-based procedure for preparing HSA nanoparticles. First, characterization by HPLC-MS and Dynamic Light Scattering (DLS) showed a good entrapment efficacy, a controllable particle size (between 100 and 200nm) and an optimal stability over time, confirmed by an in vitro drug release assay. Then, 1-4 and the corresponding NPs were tested for their antiproliferative activity against neuroblastoma SH-SY5Y cell line. Notably, 3-NPs and 4-NPs were identified as the most promising formulation showing a profitable balance of stability, small size and a similar activity compared to the free drugs in cell-based assays. In addition, albumin formulations increase the solubility of pyrazolo[3,4-d]pyrimidine avoiding the use of DMSO as solubilizing agent., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Amyloid fibrillation is a prevalent phenomenon in different proteins and peptides, which results in a variety of disorders. Over the last decade, implementation of nanoparticles (NPs), with or without drugs, is considered as a promising approach to protect against the aggregation process of amyloid proteins. In this study, we investigated the effect of human serum albumin NPs (HSA NPs) on the fibrillation of Hen Egg White Lysozyme (HEWL). The results showed that HSA NPs decrease the fibrillation of HEWL in a size dependent manner. Surprisingly, despite their inhibitory effects on the formation of long fibrils, our studies revealed that the NPs do not preserve the stability of the protein's structure in denaturing conditions. In fact, different structural analysis methods revealed that in the presence of the NPs, the protein's tendency to expose hydrophobic patches increased. Therefore, it seems that HSA NPs are responsible for decrease in HEWL fibrillation by reducing its concentration and blocking hot spot regions for self-assembly via moderate interaction. Collectively, our results shed light on the impact of HSA NPs on HEWL fibrillation and open new challenges on the implications of these NPs for drug delivery purposes or direct use as therapeutic agents., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Lapatinib, a selective small-molecule dual-tyrosine kinase inhibitor of HER2 and EGFR, is effective in HER2-positive patients with advanced metastatic breast cancer. However, its low and variable oral absorption, large required daily dose and serious gastrointestinal side effects all limit its clinical use. Intravenous administration offers a good option to overcome these disadvantages. However, the poor solubility of lapatinib in water and organic solvents causes lapatinib to fail in a common injectable preparation. Considering lapatinib's high albumin binding ability (>99%), in this study, we developed human serum albumin nanoparticles loaded with lapatinib (LHNPs) by Nab technology for intravenous administration and investigated its efficacy against HER2-positive breast cancer. Raman shift, X-ray diffraction and X-ray photoelectron spectroscopy studies demonstrated that lapatinib was successfully incorporated into nanoparticles, and LHNPs exhibited good stability and sustained-release effect in vitro. LHNPs could be effectively taken up by SKBr3 cells in a concentration- and time-dependent manner, and the uptake was mediated by energy-dependent endocytosis, which involved clathrin-dependent pinocytosis. Furthermore, in vitro and in vivo data indicated that LHNPs presented the strong ability to induce apoptosis and superior anti-tumor efficacy in tumor-bearing mice to the commercial tablet Tykerb through the inhibition of HER2 phosphorylation. Subchronic toxicity assays indicated that LHNPs had no hepatic or kidney toxicity. With mature technology for industrial production and enhanced therapeutic effects, LHNPs are likely to have great potential as a safe therapeutic candidate against HER2-positive breast cancer in the clinic., (Copyright © 2015 Elsevier B.V. All rights reserved.)

In our study, we aimed to develop a codelivery nanoparticulate system of pirarubicin (THP) and paclitaxel (PTX) (Co-AN) using human serum albumin to improve the therapeutic effect and reduce systemic toxicities. The prepared Co-AN demonstrated a narrow size distribution around 156.9 ± 3.2 nm (PDI = 0.16 ± 0.02) and high loading efficiency (87.91 ± 2.85% for THP and 80.20 ± 2.21% for PTX) with sustained release profiles. Significantly higher drug accumulation in tumors and decreased distribution in normal tissues were observed for Co-AN in xenograft 4T1 murine breast cancer bearing BALB/c mice. Cytotoxicity test against 4T1 cells in vitro and antitumor assay on 4T1 breast cancer in vivo demonstrated that the antitumor effect of Co-AN was superior to that of the single drug or free combination. Also, Co-AN induced increased apoptosis and G2/M cell cycle arrest against 4T1 cells compared to that of the single drug formulation. Remarkably, Co-AN exhibited significantly lower side effects regarding bone marrow suppression and organ and gastrointestinal toxicities. This human serum albumin-based codelivery system represents a promising platform for combination chemotherapy in breast cancers.

Treatment of Ischemic Stroke is inordinately challenging due to its complex aetiology and constraints in shuttling therapeutics across blood-brain barrier. Ropinirole hydrochloride (Rp), a propitious neuroprotectant with anti-oxidant, anti-inflammatory, and anti-apoptotic properties (3A) is repurposed for remedying ischemic stroke and reperfusion (I/R) injury. The drug's low bioavailability in brain however, limits its therapeutic efficacy. The current research work has reported sub-100 nm gamma-L-Glutamyl-L-Cysteine coated Human Serum Albumin nanoparticles encapsulating Rp (C-Rp-NPs) for active targeting in ischemic brain to encourage in situ activity and reduce unwanted toxicities. Confocal microscopy and brain distribution studies confirmed the enhanced targeting potentiality of optimized C-Rp-NPs. The pharmacokinetics elucidated that C-Rp-NPs could extend Rp retention in systemic circulation and escalate bioavailability compared with free Rp solution (Rp-S). Additionally, therapeutic assessment in transient middle cerebral occlusion (tMCAO) model suggested that C-Rp-NPs attenuated the progression of I/R injury with boosted therapeutic index at 1000 times less concentration compared to Rp-S via reinstating neurological and behavioral deficits, while reducing ischemic neuronal damage. Moreover, C-Rp-NPs blocked mitochondrial permeability transition pore (mtPTP), disrupted apoptotic mechanisms, curbed oxidative stress and neuroinflammation, and elevated dopamine levels post tMCAO. Thus, our work throws light on fabrication of rationally designed C-Rp-NPs with enormous clinical potential. [Display omitted] [ABSTRACT FROM AUTHOR]

Herein, the poorly water-soluble drug, Tamoxifen (Tmx), was loaded in the amphipathic matrix of human serum albumin (HSA) nanoparticles by a modified desolvation method. In order to enhance the drug loading (DL) and drug entrapment efficiency (DEE) (<2% and 10%, respectively), ultrasonication of Tmx-HSA mixture was performed prior to desolvation process. Tmx loading and entrapment efficiency were optimized by employment of the response surface methodology (RSM)-central composite design (CCD) of experiments. Under the optimum conditions of 1.59 mg Tmx/ml concentration, 7.76 pH and 5 h incubation of HSA-Tmx, the DL of 6.7% and DEE of 74% are achievable. Particles with the average size of 195 nm, zeta potential of -21 mV and polydispersity index of 0.09 were produced under these conditions. A more sustained Tmx release behavior was observed from polyethylene glycol (PEG) conjugated nanoparticles in comparison to the non-PEGylated ones. The short-term stability investigation showed no alteration in physicochemical properties of nanoparticles at 4 and 37 °C, but small increase in nanoparticles size was observed after three months of storage at room temperature. This is the first report for efficient production of a Tmx delivery system based on HSA nanoparticles. [ABSTRACT FROM AUTHOR]

Abstract: Human serum albumin (HSA) nanoparticles represent an attractive strategy for active targeting of therapeutics into tumor cells due to the presence of superficial functional groups. HER2 is highly expressed in a significant proportion of cancers and monoclonal antibodies (mAbs) directed against HER2 hold great promise for effective therapy. Herein, covalent coupling of a novel mAb (1F2) directed against the extracellular domain of HER2 to the surface of HSA nanoparticles was evaluated to obtain nanoparticles with highest cellular uptake. HER2 reactivity of 1F2-conjugated nanoparticles produced under different conditions was screened by an indirect ELISA and flow cytometry techniques. Monoclonal antibody thiolation with 100-fold molar excess of 2-iminothiolane and the ratio of 10:1 for the thiolated 1F2 (μg) to PEGylated nanoparticles (mg), were optimum for the attachment process. Under this condition, 23±4% of 1F2 was conjugated to nanoparticles. The flow cytometry results show that 1F2-modified nanoparticles interact with nearly all HER2 receptors on the surface of BT474 cells. In addition, no cellular uptake was observed on MCF7 cells. In vitro analyses showed no significant cytotoxicity of produced system against BT474 cells. Therefore, 1F2-attached HSA nanoparticles represent a potential delivery system for targeted transport of therapeutic agents into HER2-positive tumor cells. [Copyright &y& Elsevier]

Background: Improving the water solubility of hydrophobic drugs, increasing their accumulation in tumor tissue and allowing their simultaneous action by different pathways are essential issues for a successful chemotherapeutic activity in cancer treatment. Considering potential clinical application in the future, it will be promising to achieve such purposes by developing new biocompatible hybrid nanocarriers with multimodal therapeutic activity. Results: We designed and characterised a hybrid nanocarrier based on human serum albumin/chitosan nanoparticles (HSA/chitosan NPs) able to encapsulate free docetaxel (DTX) and doxorubicin-modified gold nanorods (DOXO-GNRs) to simultaneously exploit the complementary chemotherapeutic activities of both antineoplasic compounds together with the plasmonic optical properties of the embedded GNRs for plasmonic-based photothermal therapy (PPTT). DOXO was assembled onto GNR surfaces following a layer-by-layer (LbL) coating strategy, which allowed to partially control its release quasi-independently release regarding DTX under the use of near infrared (NIR)-light laser stimulation of GNRs. In vitro cytotoxicity experiments using triple negative breast MDA-MB-231 cancer cells showed that the developed dual drug encapsulation approach produces a strong synergistic toxic effect to tumoral cells compared to the administration of the combined free drugs; additionally, PPTT enhances the cytostatic efficacy allowing cell toxicities close to 90% after a single low irradiation dose and keeping apoptosis as the main cell death mechanism. Conclusions: This work demonstrates that by means of a rational design, a single hybrid nanoconstruct can simultaneously supply complementary therapeutic strategies to treat tumors and, in particular, metastatic breast cancers with good results making use of its stimuli-responsiveness as well as its inherent physico-chemical properties. [ABSTRACT FROM AUTHOR]