A novel polyphosphoester (PPE) with vinyl ether side chain functionality was developed as a versatile template for postpolymerization modifications, and its degradability and biocompatibility were evaluated. An organo-catalyzed ring-opening polymerization of ethylene glycol vinyl ether-pendant cyclic phosphotriester monomer allowed for construction of poly(ethylene glycol vinyl ether phosphotriester) (PEVEP). This vinyl ether-functionalized PPE scaffold was coupled with hydroxyl- or thiol-containing model small molecules via three different types of conjugation chemistries—thiol—ene “click” reaction, acetalization, or thio-acetalization reaction—to afford modified polymers that accommodated either stable thio–ether or hydrolytically labile acetal or thio–acetal linkages. Amphiphilic diblock copolymers of poly(ethylene glycol) and PEVEP formed well-defined micelles with a narrow and monomodal size distribution in water, as confirmed by dynamic light scattering (DLS), transmission electron microscopy, and atomic force microscopy. The stability of the micelles and the hydrolytic degradability of the backbone and side chains of the PEVEP block segment were assessed by DLS and nuclear magnetic resonance spectroscopy (1H and 31P), respectively, in aqueous buffer solutions at pH values of 5.0 and 7.4 and at temperatures of 25 and 37 °C. The hydrolytic degradation products of the PEVEP segments of the block copolymers were then identified by electrospray ionization, gas chromatography, and matrix-assisted laser desorption/ionization mass spectrometry. The parent micelles and their degradation products were found to be non-cytotoxic at concentrations up to 3 mg/mL, when evaluated with RAW 264.7 mouse macrophages and OVCAR-3 human ovarian adenocarcinoma cells.

The construction of nanostructures from biodegradable precursors and shell/core crosslinking have been pursued as strategies to solve the problems of toxicity and limited stability, respectively. Polyphosphoester (PPE)-based micelles and crosslinked nanoparticles with non-ionic, anionic, cationic, and zwitterionic surface characteristics for potential packaging and delivery of therapeutic and diagnostic agents, were constructed using a quick and efficient synthetic strategy, and importantly, demonstrated remarkable differences in terms of cytotoxicity, immunotoxicity, and biofouling properties, as a function of their surface characteristics and also with dependence on crosslinking throughout the shell layers. For instance, crosslinking of zwitterionic micelles significantly reduced the immunotoxicity, as evidenced from the absence of secretions of any of the 23 measured cytokines from RAW 264.7 mouse macrophages treated with the nanoparticles. The micelles and their crosslinked analogs demonstrated lower cytotoxicity than several commercially-available vehicles, and their degradation products were not cytotoxic to cells at the range of the tested concentrations. PPE-nanoparticles are expected to have broad implications in clinical nanomedicine as alternative vehicles to those involved in several of the currently available medications.

The development of well-defined polymeric nanoparticles (NPs) as delivery carriers for antimicrobials targeting human infectious diseases requires rational design of the polymer template, an efficient synthetic approach and fundamental understanding of the developed NPs, e.g., drug loading/release, particle stability, and other characteristics. Herein, we developed and evaluated the in vitro antimicrobial activity of silver-bearing, fully biodegradable and functional polymeric NPs. A series of degradable polymeric nanoparticles (dNPs), composed of phosphoester and L-lactide and designed specifically for silver loading into the hydrophilic shell and/or the hydrophobic core, were prepared as potential delivery carriers for three different types of silver-based antimicrobials – silver acetate or one of two silver carbene complexes (SCCs). Silver-loading capacities of the dNPs were not influenced by the hydrophilic block chain length, loading site (i.e., core or shell), or type of silver compound, but optimization of the silver feed ratio was crucial to maximize the silver loading capacity of dNPs, up to ca. 12% (w/w). The release kinetics of silver-bearing dNPs revealed 50% release at ca. 2.5–5.5 h depending on the type of silver compound. In addition, we undertook a comprehensive evaluation of the rates of hydrolytic or enzymatic degradability and performed structural characterization of the degradation products. Interestingly, packaging of the SCCs in the dNP-based delivery system improved minimum inhibitory concentrations up to 70%, compared with the SCCs alone, as measured in vitro against ten contemporary epidemic strains of Staphylococcus aureus and eight uropathogenic strains of Escherichia coli. We conclude that these dNP-based delivery systems may be beneficial for direct epithelial treatment and/or prevention of ubiquitous bacterial infections, including those of the skin and urinary tract.

Herein, we demonstrate the synthesis of a bicyclic carbonate monomer of a d-glucal derivative, which originated from the natural product d-glucose, in an efficient three-step procedure and its ring-opening polymerization (ROP), initiated by 4-methylbenzyl alcohol, via organocatalysis. The ROP behavior was studied as a function of time, catalyst type, and catalyst concentration by using size exclusion chromatography (SEC) and nuclear magnetic resonance (NMR) spectroscopy. Using a cocatalyst system of 1,8-diazabicyclo[5.4.0]­undec-7-ene and 1-(3,5-bis­(trifluoromethyl)­phenyl)-3-cyclohexyl-2-thiourea (5 mol %) afforded poly­(d-glucal-carbonate) (PGCC) with almost complete monomer conversion (ca. 99%) within 1 min, as analyzed by 1H NMR spectroscopy, and a monomodal SEC trace with dispersity of 1.13. The resulting PGCCs exhibited amorphous characteristics with a relatively high glass transition temperature at ca. 69 °C and onset decomposition temperature at ca. 190 °C, as analyzed by differential scanning calorimetry and thermogravimetric analysis, respectively. This new type of potentially degradable polymer system represents a reactive functional polymer architecture.

Serious lung infections, such as pneumonia, tuberculosis, and chronic obstructive cystic fibrosis-related bacterial diseases, are increasingly difficult to treat and can be life-threatening. Over the last decades, an array of therapeutics and/or diagnostics have been exploited for management of pulmonary infections, but the advent of drug-resistant bacteria and the adverse conditions experienced upon reaching the lung environment urge the development of more effective delivery vehicles. Nanotechnology is revolutionizing the approach to circumventing these barriers, enabling better management of pulmonary infectious diseases. In particular, polymeric nanoparticle-based therapeutics have emerged as promising candidates, allowing for programmed design of multi-functional nanodevices and, subsequently, improved pharmacokinetics and therapeutic efficiency, as compared to conventional routes of delivery. Direct delivery to the lungs of such nanoparticles, loaded with appropriate antimicrobials and equipped with “smart” features to overcome various mucosal and cellular barriers, is a promising approach to localize and concentrate therapeutics at the site of infection while minimizing systemic exposure to the therapeutic agents. The present review focuses on recent progress (2005 to 2015) important for the rational design of nanostructures, particularly polymeric nanoparticles, for the treatment of pulmonary infections with highlights on the influences of size, shape, composition, and surface characteristics of antimicrobial-bearing polymeric nanoparticles on their biodistribution, therapeutic efficacy, and toxicity.