Hydrophobic Modification of Poly(γ-glutamic acid) by Grafting 4-Phenyl-butyl Side Groups for the Encapsulation and Release of Doxorubicin.

The delivery of drugs is a great challenge, since most of active pharmaceutical ingredients developed today are hydrophobic and poorly water soluble. From this perspective, drug encapsulation on biodegradable and biocompatible polymers can surpass this problem. Poly(γ-glutamic acid) (PGGA), a bioedible and biocompatible polymer has been chosen for this purpose. Carboxylic side groups of PGGA have been partially esterified with 4-phenyl-butyl bromide, producing a series of aliphatic-aromatic ester derivatives with different hydrophilic-lipophilic balances. Using nanoprecipitation or emulsion/evaporation methods, these copolymers were self-assembled in a water solution, forming nanoparticles with average diameters between 89 and 374 nm and zeta potential values between -13.1 and -49.5 mV. The hydrophobic core containing 4-phenyl-butyl side groups was used for the encapsulation of an anticancer drug, such as Doxorubicin (DOX). The highest encapsulation efficiency was reached for a copolymer derived from PGGA, with a 46 mol% degree of esterification. Drug release studies carried out for 5 days at different pHs (4.2 and 7.4) indicated that DOX was released faster at pH 4.2, revealing the potential of these nanoparticles as chemotherapy agents.

A multifunctional nanotheranostic agent based on Lenvatinib for multimodal synergistic hepatocellular carcinoma therapy with remarkably enhanced efficacy.

Lenvatinib (LT), a first-line molecular targeted therapeutic drug for hepatocellular carcinoma (HCC), has been replacing the status of Sorafenib (SF) as the clinically preferred and irreplaceable treatment for a decade. To overcome the low drug utilization and limited single efficacy of LT, ultrasmall copper sulfide nanocrystals (Cu2-xS NCs), and ultrasmall gold nanoparticle (AuNPs) were evenly wrapped into galactosamine conjugated poly(lactide-co-glycolide) (PLGA) as the drug delivery nanoparticles (CAL@PG) by nanoprecipitation. The CAL@PG NPs exhibited excellent stability under physiological conditions, whereas they released LT rapidly in the unique tumor microenvironment (TME) and high temperature, which could be provided by the near-infrared-II (NIR-II) photothermal effect of Cu2-xS NCs. Moreover, the temperature elevation, regenerated hydrogen peroxide (H2O2), and lower pH of TME could substantially boost the reaction potency of copper Fenton-like chemistry. More importantly, this combined therapy significantly improved the efficacy of LT, provided a multifunctional LT delivery system, and enriched the nanoparticle-augmented multimodal synergistic HCC therapy modality.

A Highly Translatable Dual-arm Local Delivery Strategy To Achieve Widespread Therapeutic Coverage in Healthy and Tumor-bearing Brain Tissues.

Drug delivery nanoparticles (NPs) based entirely on materials generally recognized as safe that provide widespread parenchymal distribution following intracranial administration via convection-enhanced delivery (CED) are introduced. Poly(lactic-co-glycolic acid) (PLGA) NPs are coated with various poloxamers, including F68, F98, or F127, via physical adsorption to render particle surfaces non-adhesive, thereby resisting interactions with brain extracellular matrix. F127-coated PLGA (F127/PLGA) NPs provide markedly greater distribution in healthy rat brains compared to uncoated NPs and widespread coverage in orthotopically-established brain tumors. Distribution analysis of variously-sized F127/PLGA NPs determines the average rat brain tissue porosity to be between 135 and 170 nm while revealing unprecedented brain coverage of larger F127/PLGA NPs with an aid of hydraulic pressure provided by CED. Importantly, F127/PLGA NPs can be lyophilized for long-term storage without compromising their ability to penetrate the brain tissue. Further, 65- and 200-nm F127/PLGA NPs lyophilized-reconstituted and administered in a moderately hyperosmolar infusate solution show further enhance particle dissemination in the brain via osmotically-driven enlargement of the brain tissue porosity. Combination of F127/PLGA NPs and osmotic tissue modulation provides a means with a clear regulatory path to maximize the brain distribution of large NPs that enable greater drug loading and prolong drug release.

Silver-loaded mesoporous silica nanoparticles enhanced the mechanical and antimicrobial properties of 3D printed denture base resin.

The aim of this study is to develop a novel 3D printed denture base resin material modified with mesoporous silica nanocarrier loaded with silver (Ag/MSN) to enhance mechanical and antimicrobial properties. Acrylate resin-based was incorporated with various proportion of Ag/MSN (0.0-2.0 wt%). Specimens with different geometry were printed and characterized accordingly for the effect of modification on properties such as: mechanical and physical properties, chemical composition and degree of conversion, as well as biological response in term of biocompatibility and antimicrobial against oral fibroblast and candida biofilm (C. albicans), respectively. The consecutive addition of Ag/MSN improved significantly surface hardness and crack propagation resistance, while flexural strength remained similar to control; however, a negligible decrease was observed with higher concentrations ≥1 wt%. No significant difference was noticed with water sorption, while water solubility had a remarkable trend of reduction associated with filler content. The surface roughness significantly increased when concentration of Ag/MSN was ≥1.0 wt%. A significant reduction in C. albicans biofilm mass, as the inhibition proficiency was correlated with the proportion of the filler. With respect to the amount of Ag/MSN, the modification was compatible toward fibroblast cells. The sequential addition of Ag/MSN enhanced significantly the mechanical and antimicrobial properties of the 3D printed resin-based material without affecting adversely compatibility. The acrylic resin denture base material has susceptibility of microbial adhesion which limits its application. Silver loaded MSN showed a significant performance to enhance antimicrobial activity against C. albicans which is the main cause of denture stomatitis. The proposed invention is a promise technique for clinical application to provide an advanced prosthesis fabrication and serve as long-term drug delivery.

Indocyanine green/doxorubicin-encapsulated functionalized nanoparticles for effective combination therapy against human MDR breast cancer.

To overcome low therapeutic efficacy of chemotherapy against multidrug resistance (MDR) breast cancer, a combination therapy system based upon functionalized polymer nanoparticles comprising poly(γ-glutamic acid)-g-poly(lactic-co-glycolic acid) (γ-PGA-g-PLGA) as the major component was developed. The NPs were loaded with doxorubicin (DOX) and indocyanine green (ICG) for dual modality cancer treatment and coated with cholesterol-PEG (C-PEG) for MDR abrogation in treatment of human MDR breast cancer. The in vitro cellular uptake of the DOX/ICG loaded nanoparticles (DI-NPs) by MDR cancer cells was significantly enhanced owing to effective inhibition of the P-gp activity by C-PEG and γ-PGA receptor-mediated endocytosis. DOX localization in cytoplasm and nucleus was observed particularly with the photo-thermal effect that facilitated intracellular drug release. As a result, the C-PEG coated DI-NPs after photo-irradiation exhibited a synergistic effect of combination (chemo/thermal) therapy to depress the proliferation of MDR cancer calls. The ex vivo biodistribution study revealed an enhanced tumor accumulation of C-PEG (2000) coated DI-NPs in MCF-7/MDR tumor-bearing nude mice due to the excellent EPR effects by the NP surface PEGylation. The MDR tumor growth was almost entirely inhibited in the group receiving combination therapy from CP2k-DI-NPs and photo-irradiation along with substantial cell apoptosis of tumor tissues examined by immunohistochemical staining. The results demonstrate a promising dual modality therapy system, CP2k-DI-NPs, developed in this work for effective combination therapy of human MDR breast cancer.

Hydrophilic interaction liquid chromatography-tandem mass spectrometry quantitative method for the cellular analysis of varying structures of gemini surfactants designed as nanomaterial drug carriers.

Diquaternary gemini surfactants have successfully been used to form lipid-based nanoparticles that are able to compact, protect, and deliver genetic materials into cells. However, what happens to the gemini surfactants after they have released their therapeutic cargo is unknown. Such knowledge is critical to assess the quality, safety, and efficacy of gemini surfactant nanoparticles. We have developed a simple and rapid liquid chromatography electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) method for the quantitative determination of various structures of gemini surfactants in cells. Hydrophilic interaction liquid chromatography (HILIC) was employed allowing for a short simple isocratic run of only 4min. The lower limit of detection (LLOD) was 3ng/mL. The method was valid to 18 structures of gemini surfactants belonging to two different structural families. A full method validation was performed for two lead compounds according to USFDA guidelines. The HILIC-MS/MS method was compatible with the physicochemical properties of gemini surfactants that bear a permanent positive charge with both hydrophilic and hydrophobic elements within their molecular structure. In addition, an effective liquid-liquid extraction method (98% recovery) was employed surpassing previously used extraction methods. The analysis of nanoparticle-treated cells showed an initial rise in the analyte intracellular concentration followed by a maximum and a somewhat more gradual decrease of the intracellular concentration. The observed intracellular depletion of the gemini surfactants may be attributable to their bio-transformation into metabolites and exocytosis from the host cells. Obtained cellular data showed a pattern that grants additional investigations, evaluating metabolite formation and assessing the subcellular distribution of tested compounds.

Recovery of Drug Delivery Nanoparticles from Human Plasma Using an Electrokinetic Platform Technology.

The effect of complex biological fluids on the surface and structure of nanoparticles is a rapidly expanding field of study. One of the challenges holding back this research is the difficulty of recovering therapeutic nanoparticles from biological samples due to their small size, low density, and stealth surface coatings. Here, the first demonstration of the recovery and analysis of drug delivery nanoparticles from undiluted human plasma samples through the use of a new electrokinetic platform technology is presented. The particles are recovered from plasma through a dielectrophoresis separation force that is created by innate differences in the dielectric properties between the unaltered nanoparticles and the surrounding plasma. It is shown that this can be applied to a wide range of drug delivery nanoparticles of different morphologies and materials, including low-density nanoliposomes. These recovered particles can then be analyzed using different methods including scanning electron microscopy to monitor surface and structural changes that result from plasma exposure. This new recovery technique can be broadly applied to the recovery of nanoparticles from high conductance fluids in a wide range of applications.