A self-immolative linker for the pH-responsive release of amides

The administration of therapeutics using bioconjugation has been mainly limited to drugs containing amine, alcohol, or thiol functional groups. Here, we report a general procedure for the preparation of benzylic N-acyl carbamates suitable for masking the amide group in important drugs such as Linezolid, Enzalutamide, or Tasimelteon in good to acceptable yields. These N-acyl carbamates appear to be stable in plasma, while a qualitative analysis of further drug uncage demonstrates that, at pH values of 5.5, a classical 1,6-benzyl elimination mechanism takes place, releasing more than 80% of the drug in 24 h. © 2023 by the authors

PH-responsive release of chlorhexidine from modified nanoporous silica nanoparticles for dental applications

A pH-sensitive stimulus-response system for controlled drug release was prepared by modifying nanoporous silica nanoparticles (NPSNPs) with poly(4-vinylpyridine) using a bismaleimide as linker. At physiological pH values, the polymer serves as gate keeper blocking the pore openings to prevent the release of cargo molecules. At acidic pH values as they can occur during a bacterial infection, the polymer strains become protonated and straighten up due to electrostatic repulsion. The pores are opened and the cargo is released. The drug chlorhexidine was loaded into the pores because of its excellent antibacterial properties and low tendency to form resistances. The release was performed in PBS and diluted hydrochloric acid, respectively. The results showed a considerably higher release in acidic media compared to neutral solvents. Reversibility of this pH-dependent release was established. In vitro tests proved good cytocompatibility of the prepared nanoparticles. Antibacterial activity tests with Streptococcus mutans and Staphylococcus aureus revealed promising perspectives of the release system for biofilm prevention. The developed polymer-modified silica nanoparticles can serve as an efficient controlled drug release system for long-term delivery in biomedical applications, such as in treatment of biofilm-associated infections, and could, for example, be used as medical implant coating or as components in dental composite materials

Evaluation of liposomes coated with a pH responsive polymer

Liposomes have been coated with the pH responsive polymer, Eudragit S100, and the formulation's potential for lower gastrointestinal (GI) targeting following oral administration assessed. Cationic liposomes were coated with the anionic polymer through simple mixing. The evolution of a polymer coat was studied using zeta potential measurements and laser diffraction size analysis. Further evidence of an association between polymer and liposome was obtained using light and cryo scanning electron microscopy. Drug release studies were carried out at pH 1.4, pH 6.3 and pH 7.8, representing the pH conditions of the stomach, small intestine and ileocaecal junction, respectively.\ud \ud The polymer significantly reduced liposomal drug release at pH 1.4 and pH 6.3 but drug release was equivalent to the uncoated control at pH 7.8, indicating that the formulation displayed appropriate pH responsive release characteristics. While the coating layer was not able to withstand the additional challenge of bile salts this reinforces the importance of evaluating these types of formulations in more complex media.\ud \u

Curcumin Sustained Release with a Hybrid Chitosan-Silk Fibroin Nanofiber Containing Silver Nanoparticles as a Novel Highly Efficient Antibacterial Wound Dressing

Drug loading in electrospun nanofibers has gained a lot of attention as a novel method for direct drug release in an injury site to accelerate wound healing. The present study deals with the fabrication of silk fibroin (SF)-chitosan (CS)-silver (Ag)-curcumin (CUR) nanofibers using the electrospinning method, which facilitates the pH-responsive release of CUR, accelerates wound healing, and improves mechanical properties. Response surface methodology (RSM) was used to investigate the effect of the solution parameters on the nanofiber diameter and morphology. The nanofibers were characterized via Fourier Transform Infrared Spectroscopy (FTIR), X-ray Diffraction (XRD), Scanning Electron Microscopy (SEM), zeta potential, and Dynamic Light Scattering (DLS). CS concentration plays a crucial role in the physical and mechanical properties of the nanofibers. Drug loading and entrapment efficiencies improved from 13 to 44% and 43 to 82%, respectively, after the incorporation of Ag nanoparticles. The application of CS hydrogel enabled a pH-responsive release of CUR under acid conditions. The Minimum Inhibitory Concentration (MIC) assay on E. coli and S. aureus bacteria showed that nanofibers with lower CS concentration cause stronger inhibitory effects on bacterial growth. The nanofibers do not have any toxic effect on cell culture, as revealed by in vitro wound healing test on NIH 3T3 fibroblasts

Eudragit® L100/chitosan composite thin bilayer films for intravaginal pH-responsive release of Tenofovir

[EN] The high rate of HIV new infections and AIDS-related deaths each year make prevention tools still necessary today. Different dosage forms – including films – for vaginal administration of antiretroviral drugs have been developed for this purpose. Six batches of Tenofovir-loaded films were formulated based on Eudragit® L100 (EL100) and chitosan, containing triethyl citrate and glycerol. In all the cases films structured in two layers – the upper layer mainly attributed to EL100 and the lower layer to chitosan – were revealed by SEM. A higher content in EL100 and plasticizers improves the mechanical properties and control over drug release in the vaginal medium without affecting mucoadhesion. The EL100-based layer acts as a structuring agent that controls Tenofovir release for days in the vaginal medium while it occurs in a few hours in the presence of seminal fluid. Bilayer films with the highest tested content of EL100 and plasticizers would be the most suitable as vaginal microbicides as they are easier to administer due to their excellent mechanical properties and they offer more comfortable posology and enhanced protection against HIV during intercourse due to their pH-responsive release of Tenofovir.This work was supported by the Spanish Research Agency and the European Regional Development Fund (AEI/FEDER, UE) [MAT2016-76416-R]

Ph-responsive release of ruthenium metallotherapeutics from mesoporous silica-based nanocarriers

Ruthenium complexes are attracting interest in cancer treatment due to their potent cytotoxic activity. However, as their high toxicity may also affect healthy tissues, efficient and selective drug delivery systems to tumour tissues are needed. Our study focuses on the construction of such drug delivery systems for the delivery of cytotoxic Ru(II) complexes upon exposure to a weakly acidic environment of tumours. As nanocarriers, mesoporous silica nanoparticles (MSN) are utilized, whose surface is functionalized with two types of ligands, (2-thienylmethyl)hydrazine hydrochloride (H1) and (5,6-dimethylthieno[2,3-d]pyrimidin-4-yl)hydrazine (H2), which were attached to MSN through a pH-responsive hydrazone linkage. Further coordination to ruthenium(II) center yielded two types of nanomaterials MSN-H1[Ru] and MSN-H2[Ru]. Spectrophotometric measurements of the drug release kinetics at different pH (5.0, 6.0 and 7.4) confirm the enhanced release of Ru(II) complexes at lower pH values, which is further supported by inductively coupled plasma optical emission spectrometry (ICP-OES) measurements. Furthermore, the cytotoxicity effect of the released metallotherapeutics is evaluated in vitro on metastatic B16F1 melanoma cells and enhanced cancer cell-killing efficacy is demonstrated upon exposure of the nanomaterials to weakly acidic conditions. The obtained results showcase the promising capabilities of the designed MSN nanocarriers for the pH-responsive delivery of metallotherapeutics and targeted treatment of cancer.Supplementary material: [https://cer.ihtm.bg.ac.rs/handle/123456789/4573

pH Responsive Polymeric Nanoparticles for Oral Insulin Delivery

Gelatin-eudragit L100 nanoparticles of wet size range 170-563nm were prepared by two step dissolvation method and the effect of different concentrations of eudragit L100 and emulsifying agent - sodium lauryl sulphate (SLS) - on the particle size were studied. Synthesized nanoparticles were characterized by attenuated total reflectance-fourier transform infrared spectroscopy (ATRFTIR) and the mean size distribution. Insulin loading was done at a pH 7.4 and the in vitro insulin release studies of nanoparticles were carried out by simulating gastrointestinal tract condition which showed the minimal insulin release at pH 2.5 (20% in 90min) while appreciable release (40% in first 30min) at pH of 7.4. This pH responsive release pattern of the synthesized nanoparticles confers on the insulin protection from proteolytic degradation in acidic environment of stomach and upper intestinal part while enhancing bioavailability in the later part of intestine

Calcium phosphate coated core-shell protein nanocarriers: Robust stability, controlled release and enhanced anticancer activity for curcumin delivery

Composite protein and inorganic nanodelivery systems can realise a pH-responsive release and effectively improve the stability and anti-cancer proliferative activity of hydrophobic molecules. In this study, a novel core-shell structure of NaCas (Sodium Caseinate)@CaP (Calcium Phosphate) as a nanodelivery system with NaCas as the core for increasing solubility and CaP as the shell for enhanced stability was built. By using Cur (Curcumin) as a model bioactive molecule, (Cur@NaCas)@CaP nanoparticles (NPs) demonstrated a uniform size distribution of 150–200 nm with a distinct nano-composite structure. After exposure to 80 °C for 2 h, the NaCas@CaP loaded Cur still retained 80% stability while under the same conditions only 12% of free Cur remained intact. UV-light stability was remarkably enhanced 8.56 fold by the protection of the core-shell structure. More importantly, pH-responsive release was achieved owing to the CaP surface coating. The encapsulated Cur by NaCas@CaP NPs exhibited an enhanced cellular anti-oxidant activity (CAA) based on MGC-803 cell monolayer models. The confocal laser-scanning microscopy (CLSM) images and cancer-cell-proliferation assay illustrated that (Cur@NaCas)@CaP NPs showed significantly improvements of cellular uptake and anti-cancer activity against A549 cancer cells than free Cur. These novels core-shell NaCas@CaP NPs are very promising for intensifying the stability and bioactivity of hydrophobic compounds in drug delivery and cancer treatment

Polyelectrolyte complex micelles by self-assembly of polypeptide-based triblock copolymer for doxorubicin delivery

AbstractPolyelectrolyte complex micelles were prepared by self-assembly of polypeptide-based triblock copolymer as a new drug carrier for cancer chemotherapy. The triblock copolymer, poly(l-aspartic acid)-b-poly(ethylene glycol)-b-poly(l-aspartic acid) (PLD-b-PEG-b-PLD), spontaneously self-assembled with doxorubicin (DOX) via electrostatic interactions to form spherical micelles with a particle size of 60–80 nm (triblock ionomer complexes micelles, TBIC micelles). These micelles exhibited a high loading capacity of 70% (w/w) at a drug/polymer ratio of 0.5 at pH 7.0. They showed pH-responsive release patterns, with higher release at acidic pH than at physiological pH. Furthermore, DOX-loaded TBIC micelles exerted less cytotoxicity than free DOX in the A-549 human lung cancer cell line. Confocal microscopy in A-549 cells indicated that DOX-loaded TBIC micelles were transported into lysosomes via endocytosis. These micelles possessed favorable pharmacokinetic characteristics and showed sustained DOX release in rats. Overall, these findings indicate that PLD-b-PEG-b-PLD polypeptide micelles are a promising approach for anti-cancer drug delivery

Asymetric Triblock Copolymer Nanocarriers for Controlled Localization and pH-Sensitive Release of Proteins

Designing nanocarriers to release proteins under specific conditions is required to improve therapeutic approaches, especially in treating cancer and protein deficiency diseases. We present here supramolecular assemblies based on asymmetric poly(ethylene glycol)-b-poly(methylcaprolactone)-b-poly(2-(N,Ndiethylamino)ethyl methacrylate) (PEG-b-PMCL-b-PDMAEMA) copolymers for controlled localization and pH-sensitive release of proteins. Copolymers self-assembled in soft nanoparticles with a core domain formed by PMCL, and a hydrophilic domain based on PEG mainly embedded inside, and the branched PDMAEMA exposed at the particle surface. We selected as model proteins to be attached to the nanoparticles bovine serum albumin (BSA) and acid sphingomyelinase (ASM), the latter being an ideal candidate for protein replacement therapy. The hydrophilic/hydrophobic ratio, nanoparticle size, and the nature of biomolecules are key factors for modulating protein localization and attachment efficiency. The predominant outer shell of PDMAEMA allows efficient pH-triggered release of BSA and ASM, and in acidic conditions >70% of the bound proteins were released. Uptake of protein-attached nanoparticles by HELA cells, together with low toxicity and pH-responsive release, supports such protein-bound nanoparticles as efficient stimuli-responsive candidates for protein therapy