'Click' synthesis of dextran macrostructures for combinatorial-designed self-assembled nanoparticles encapsulating diverse anticancer therapeutics.

With the non-specific toxicity of anticancer drugs to healthy tissues upon systemic administration, formulations capable of enhanced selectivity in delivery to the tumor mass and cells are highly desirable. Based on the diversity of the drug payloads, we have investigated a combinatorial-designed strategy where the nano-sized formulations are tailored based on the physicochemical properties of the drug and the delivery needs. Individually functionalized C(2) to C(12) lipid-, thiol-, and poly(ethylene glycol) (PEG)-modified dextran derivatives were synthesized via 'click' chemistry from O-pentynyl dextran and relevant azides. These functionalized dextrans in combination with anticancer drugs form nanoparticles by self-assembling in aqueous medium having PEG surface functionalization and intermolecular disulfide bonds. Using anticancer drugs with logP values ranging from -0.5 to 3.0, the optimized nanoparticles formulations were evaluated for preliminary cellular delivery and cytotoxic effects in SKOV3 human ovarian adenocarcinoma cells. The results show that with the appropriate selection of lipid-modified dextran, one can effectively tailor the self-assembled nano-formulation for intended therapeutic payload.

Combinatorial-designed multifunctional polymeric nanosystems for tumor-targeted therapeutic delivery.

By definition, multifunctional nanosystems include several features within a single construct so that these devices can target tumors or other disease tissue, facilitate in vivo imaging, and deliver a therapeutic agent. Investigations of these nanosystems are rapidly progressing and provide new opportunities in the management of cancer. Tumor-targeted nanosystems are currently designed based primarily on the intrinsic physico-chemical properties of off-the-shelf polymers. Following fabrication, the surfaces of these nanoscale structures are functionalized for passive or active targeted delivery to the tumors. In this Account, we describe a novel approach for the construction of multifunctional polymeric nanosystems based on combinatorial design principles. Combinatorial approaches offer several advantages over conventional methods because they allow for the integration of multiple components with varied properties into a nanosystem via self-assembly or chemical conjugation. High-throughput synthesis and screening is required in polymer design because polymer composition directly affects properties including drug loading, retention in circulation, and targeting of the nanosystems. The first approach relies on the self-assembly of macromolecular building blocks with specific functionalities in aqueous media to yield a large variety of nanoparticle systems. These self-assembled nanosystems with diverse functionalities can then be rapidly screened in a high-throughput fashion for selection of ideal formulations, or hits, which are further evaluated for safety and efficacy. In another approach, a library of a large number of polymeric materials is synthesized using different monomers. Each of the formed polymers is screened for the selection of the best candidates for nanoparticle fabrication. The combinatorial design principles allow for the selection of those nanosystems with the most favorable properties based on the type of payload, route of administration, and the desired target for imaging and delivery.

Drug delivery approaches to overcome bacterial resistance to beta-lactam antibiotics.

BACKGROUND: Since its landmark discovery in 1928, penicillin has had a profound impact on the quality of human life. The ability to treat and cure deadly infections and bacterial diseases has forever changed our medical profession and way of life, providing unprecedented relief from pain, suffering, and death due to microbial infection. Penicillin and its many derivatives have dominated the field of antibiotics research and development, while demonstrating unprecedented success as a therapeutic used around the world. The beta-lactams, as a family of more than six structural variants all having the 2-azetidinone ring, have worked extremely well against a wide variety of disease-causing pathogens, while exerting little if any toxicity towards mammalian cells. Penicillin has truly been a wonder drug. However, over the last 60 years, drug resistance to the penicillins has steadily been increasing in frequency and severity, to the point where today there are grave concerns that the beta-lactams will soon no longer be able to stop deadly bacterial infections. OBJECTIVE: The aim of this discussion is to present what has been investigated as a means to enhance the performance of beta-lactam antibiotics against drug-resistant bacteria, and what is currently being explored or is likely to prove useful in the future. METHODS: This review provides a descriptive overview of the various published ways to enhance the clinical effectiveness of beta-lactam antibiotics, beginning with the early and ongoing search for more powerful beta-lactam derivatives, penicillinase-stable variants, beta-lactam prodrugs, intracellular delivery approaches, nanocarrier-based strategies, and new beta-lactams with an alternative mechanism of action. CONCLUSION: Of the progress made so far to develop approaches to overcome bacterial resistance to beta-lactams, the use of drug carriers such as liposomes and nanoparticles seems to hold significant promise, as do structural variants that operate through different biological modes of action.

Glyconanobiotics: Novel carbohydrated nanoparticle antibiotics for MRSA and Bacillus anthracis.

This report describes the synthesis and evaluation of glycosylated polyacrylate nanoparticles that have covalently-bound antibiotics within their framework. The requisite glycosylated drug monomers were prepared from one of three known antibiotics, an N-sec-butylthio beta-lactam, ciprofloxacin, and a penicillin, by acylation with 3-O-acryloyl-1,2-O-isopropylidene-5,6 bis((chlorosuccinyl)oxy)-d-glucofuranose (7) or 6-O-acetyl-3-O-acryloyl-1,2-O-isopropylidene-5-(chlorosuccinyl)oxy-alpha-d-glucofuranose (10). These acrylated monomers were subjected to emulsion polymerization in a 7:3 (w:w) mixture of butyl acrylate-styrene in the presence of sodium dodecyl sulfate as surfactant (3 weight %) and potassium persulfate as a radical initiator (1 weight %). The resulting nanoparticle emulsions were characterized by dynamic light scattering and found to have similar diameters ( approximately 40 nm) and size distributions to those of our previously studied systems. Microbiological testing showed that the N-sec-butylthio beta-lactam and ciprofloxacin nanoparticles both have powerful in vitro activities against methicillin-resistant Staphylococcus aureus and Bacillus anthracis, while the penicillin-bound nanoparticles have no antimicrobial activity. This indicates the need for matching a suitable antibiotic with the nanoparticle carrier. Overall, the study shows that even relatively large, polar acrylate monomers (MW>1000 amu) can be efficiently incorporated into the nanoparticle matrix by emulsion polymerization, providing opportunities for further advances in nanomedicine.

Penicillin-bound polyacrylate nanoparticles: restoring the activity of beta-lactam antibiotics against MRSA.

This report describes the preparation of antibacterially active emulsified polyacrylate nanoparticles in which a penicillin antibiotic is covalently conjugated onto the polymeric framework. These nanoparticles were prepared in water by emulsion polymerization of an acrylated penicillin analogue pre-dissolved in a 7:3 (w:w) mixture of butyl acrylate and styrene in the presence of sodium dodecyl sulfate (surfactant) and potassium persulfate (radical initiator). Dynamic light scattering analysis and atomic force microscopy images show that the emulsions contain nanoparticles of approximately 40 nm in diameter. The nanoparticles have equipotent in vitro antibacterial properties against methicillin-susceptible and methicillin-resistant forms of Staphylococcus aureus and indefinite stability toward beta-lactamase.

Glycosylated polyacrylate nanoparticles by emulsion polymerization.

A selection of glycosylated polyacrylate nanoparticles has been prepared by radical-initiated emulsion polymerization in aqueous media. Using ethyl acrylate as a co-monomer, carbohydrate acrylates were incorporated into the poly(ethyl acrylate) framework to give stable emulsions of glyconanoparticles with an average particle size of around 40 nm. Using this technique a variety of glyconanoparticles were prepared from 3-O-acryloyl-1,2:5,6-di-O-isopropylidene-alpha-D-glucofuranose, 1-O-acryloyl-2,3:5,6-di-O-isopropylidene-alpha-D-mannofuranose, 6-O-acryloyl-1,2:3,4-di-O-isopropylidene-alpha-D-galactopyranose, 2-N-acryloyl-1,3,4,6-tetra-O-acetyl-beta-D-glucosamine, 5-O-acryloyl-2,3-isopropylidene-1-methoxy-beta-D-ribofuranose and 4-N-acetyl-5'-O-acryloyl-2',3'-O-isopropylidene cytidine. Scanning electron microscopy, dynamic light scattering and proton NMR analysis of the emulsions indicated essentially 100% incorporation of the carbohydrate acrylate monomer into the polymer with the exception of O-benzyl- and O-benzoyl-protected carbohydrate acrylates, which gave incomplete incorporation. Formation of larger glyconanoparticles of ~80nm with (unprotected) 3-O-acryloyl-D-glucose and 5-O-acryloyl-1-methoxy-beta-D-ribofuranose revealed the influence of free hydroxyl groups in the monomer on the particle size during polymerization, a feature which is also apparently dependent on the amount of carbohydrate in the matrix. This methodology allows for a new, simple route to the synthesis of polymeric glyconanoparticles with potential applications in targeted drug delivery and materials development.