Engineered High-Loaded Mixed-Monoclonal Antibodies (Adalimumab, Rituximab and Trastuzumab) Polymeric Nanoparticle for Rheumatoid Arthritis Treatment: A Proof of Concept.

Rheumatoid arthritis, a chronic disease, affects from 0.5% to 1% of the world population. The main consequences include loss of joint functionality and severe pain, with lost in life quality and increased risk of morbidity and mortality. The main strategy for RA treatment relies in early diagnosis as targeted therapy. In this regard, the development and application of designed/engineered nanoparticles may represent an innovative approach and the key to success, since is a personalized nanodrug. Thus, we have synthetized, characterized, and in vivo evaluated a tri-loaded monoclonal antibody nanoparticle. For the production we used a mix of monoclonal antibodies: adalimumab, rituximab and trastuzumab to surround all RA metabolic pathways. The characterization included atomic force microscopy, dynamic light scattering analysis and entrapment efficacy using BCA analysis. The in vivo evaluation was done in mice. At this stage we used animals to assess the pharmacokinetics, the tissue distribution as the proof of concept (therapeutic efficacy) of the nanoparticles developed in inducted animals with rheumatoid arthritis. The interpretation of our results revealed that a spherical shaped nanoparticle has been produced with a mean size of 229.7 nm, and a polydispersity index of 0.191. This data has been corroborated by DLS and AFM analysis. The pre-clinical (in vivo) evaluation demonstrated a low elimination rate of 2,34 L/hour, with a purge of 0,42 h. The therapeutic efficacy showed that the nanoparticles have an increased therapeutic effect than the conventional drug with a reduction in all main parameters including the interleukins.

PLGA nanoparticles introduction into mitoxantrone-loaded ultrasound-responsive liposomes: In vitro and in vivo investigations.

A novel ultrasound-responsive liposomal system for tumor targeting was prepared in order to increase the antitumor efficacy and decrease serious side effects. In this paper, PLGA nanoparticles were used ultrasound-responsive agents instead of conventional microbubbles. The PLGA-nanoparticles were prepared by an emulsion solvent evaporation method. The liposomes were prepared by a lipid film hydration method. Particle size, zeta potential, encapsulation efficiency and drug loading capacity of the liposomes were studied by light scattering analysis and dialysis. Transmission electron microscopy (TEM) and atomic force microscope (AFM) were used to investigate the morphology of liposomes. The release in vitro was carried out in the pH 7.4 phosphate buffer solutions, as a result, liposome L3 encapsulating PLGA-nanoparticles displayed good stability under simulative physiological conditions and quickly responsive release under the ultrasound. The release in vivo was carried out on the rats, as a result, liposome L3 showed higher bioavailability than traditional intravenous injectable administration, and liposome L3 showed higher elimination ratio after stimulation by ultrasound than L3 without stimulation. Thus, the novel ultrasound-responsive liposome encapsulating PLGA-nanoparticles has a potential to be developed as a new drug delivery system for anti-tumor drug.

Synthesis and Anti-cancer Activity of 3-substituted Benzoyl-4-substituted Phenyl-1H-pyrrole Derivatives.

BACKGROUND: Cancer is considered a major public health problem worldwide. OBJECTIVE: The aim of this paper is to design and synthesis of novel anticancer agents with potent anticancer activity and minimum side effects. METHOD: A series of pyrrole derivatives were synthesized, their anti-cancer activity against nine cancer cell lines and two non-cancer cell lines were evaluated by MTT assay, and their cell cycle progression were determined by flow cytometry analysis. RESULTS: The study of the structure-activity relationships revealed that the introduction of the electron-donation groups at the 4th position of the pyrrole ring increased the anti-cancer activity. Among the synthesized compounds, specially the compounds bearing 3,4-dimethoxy phenyl at the 4th position of the pyrrole ring showed potent anti-cancer activity, cpd 19 was the most potent against MGC 80-3, HCT-116 and CHO cell lines (IC50s = 1.0－1.7 µM), cpd 21 was the most potent against HepG2, DU145 and CT-26 cell lines (IC50s = 0.5－0.9 µM), and cpd 15 was the most potent against A549 (IC50 = 3.6 µM). Moreover, these potent compounds showed weak cytotoxicity against HUVEC and NIH/3T3. Thus, the cpds 15, 19 and 21 show potential anti-cancer for further investigation. Furthermore, the flow cytometry analysis revealed that cpd 21 arrested the CT-26 cells at S phase, and induced the cell apoptosis. CONCLUSION: Thus, these compounds with the potent anticancer activity and low toxicity have potential for the development of new anticancer chemotherapy agents.

Synthesis and Anticancer Activity of 3-(Substituted Aroyl)-4-(3,4,5-trimethoxyphenyl)-1H-pyrrole Derivatives.

A series of 3-(substituted aroyl)-4-(3,4,5-trimethoxyphenyl)-1H-pyrrole derivatives were synthesized and determined for their anticancer activity against eleven cancer cell lines and two normal tissue cell lines using MTT assay. Among the synthesized compounds, compound 3f was the most potent compound against A375, CT-26, HeLa, MGC80-3, NCI-H460 and SGC-7901 cells (IC50  = 8.2 - 31.7 µm); 3g, 3n and 3a were the most potent compounds against CHO (IC50  = 8.2 µm), HCT-15 (IC50  = 21 µm) and MCF-7 cells (IC50  = 18.7 µm), respectively. Importantly, all the target compounds showed no cytotoxicity towards the normal tissue cell (IC50  > 100 µm). Thus, these compounds with the potent anticancer activity and low toxicity have potential for the development of new anticancer chemotherapy agents.

Structures and correlation functions of multicomponent and polydisperse hard-sphere mixtures from a density functional theory.

The structures of nonuniform binary hard-sphere mixtures and the correlation functions of uniform ternary hard-sphere mixtures were studied using a modified fundamental-measure theory based on the weight functions of Rosenfeld [Rosenfeld, Phys. Rev. Lett. 63, 980 (1989)] and Boublik-Mansoori-Carnahan-Starling-Leland equation of state [Boublik, J. Chem. Phys. 53, 471 (1970); Mansoori et al., J. Chem. Phys. 54, 1523 (1971)]. The theoretical predictions agreed very well with the molecular simulations for the overall density profiles, the local compositions, and the radial distribution functions of uniform as well as inhomogeneous hard-sphere mixtures. The density functional theory was further extended to represent the structure of a polydisperse hard-sphere fluid near a hard wall. Excellent agreement was also achieved between theory and Monte Carlo simulations. The density functional theory predicted oscillatory size segregations near a hard wall for a polydisperse hard-sphere fluid of a uniform size distribution.