Abstract Prior studies suggested that nanoparticle drug delivery might improve the therapeutic response to anticancer drugs and allow simultaneous monitoring of uptake by tumors. We employed modified PAMAM dendritic polymers <5 nm in diameter as carriers. Acetylated dendrimers were conjugated folic acid a targeting agent then coupled either methotrexate or tritium fluorescein 6-carboxytetramethylrhodamine. These conjugates injected i.v. into immunodeficient mice bearing human KB...

The maleimide motif is widely used for the selective chemical modification of cysteine residues in proteins. Despite widespread utilization, there are some potential limitations, including irreversible nature reaction and, hence, and number attachment positions. We conceived a new class which would address these limitations provide opportunities protein modification. report herein use mono- dibromomaleimides reversible illustrate this on SH2 domain Grb2 adaptor (L111C). After initial with...

Targeting protein degradation with Proteolysis-Targeting Chimeras (PROTACs) is an area of great current interest in drug discovery. Nevertheless, although the high effectiveness PROTACs against a wide variety targets has been established, most degraders reported to date display limited intrinsic tissue selectivity and do not discriminate between cells different types. Here, we describe strategy for selective specific cell type. We report design synthesis trastuzumab-PROTAC conjugate...

Two nontoxic, antimicrobial nanoemulsions, BCTP and 401, have been developed. These emulsions are composed of detergents oils in 80% water. diluted up to 1 : 1000 inactivated 190% Bacillus anthracis spores 4 h was also sporicidal against three other species. This activity is due disruption the spore coat after initiation germination without complete outgrowth. 401 had greater than an onset action <30 min. Mixing or with cereus prior subcutaneous injection mice reduced resulting skin lesion...

To investigate the uptake of a poly(amidoamine) dendrimer (generation 5 [G5]) nanoparticle covalently conjugated to polyvalent folic acid (FA) as targeting ligand into macrophages, and activity an FA- methotrexate (MTX)-conjugated (G5-FA-MTX) therapeutic for inflammatory disease arthritis.

A series of dibromomaleimides have been shown to be very efficacious at insertion into peptidic disulfide bonds. This conjugation proceeds with a stoichiometric balance reagents in buffered solutions less than 15 min give discrete products while maintaining the bridge and thus peptide conformation. The is initiated by reduction using water-soluble phosphine, tris(2-carboxyethyl)phosphine (TCEP) which allows for subsequent substitution two maleimide bromides generated thiols. Reaction salmon...

The advent of Adcetris™ and Kadcyla™, two recently FDA-approved antibody-drug conjugates (ADCs), in the clinic has had a major impact on treatment lymphoma breast cancer patients, respectively, worldwide. Despite these successes many new ADCs fail at various stages development, often due to shortcomings methods used for their assembly. To address this problem we have developed next generation maleimides (NGMs), which specifically re-bridge reduced interchain disulfide bonds allow efficient...

The introduction of non-natural entities into proteins by chemical modification has numerous applications in fundamental biological science and for the development manipulation peptide protein therapeutics. reduction native disulfide bonds provides a convenient method to access two nucleophilic cysteine residues that can serve as ideal attachment points such modification. optimum bioconjugation strategy utilizing these should include reconstruction bridge mimic role bond, maintaining...

A next generation maleimide–ADC is shown to have excellent stability in blood serum, as well high potency and selectivity <italic>in vitro</italic>.

Controlling maleimide hydrolysis allows the modular construction of bromomaleimide-mediated bioconjugates which are either stable or cleavable in an aqueous, thiol-mediated reducing environment.

Bromomaleimides react rapidly and selectively with cysteine to afford thiomaleimides which can be cleaved a phosphine regenerate the or treated base dehydroalanine.

Bromopyridazinedione-mediated bioconjugation to a cysteine containing protein and disulfide peptide is described. The conjugates are cleavable in an excess of thiol, including cytoplasmically-relevant concentrations glutathione, show high level hydrolytic stability. constructs have the potential for four points chemical attachment.

A next-generation disulfide stapling reagent, incorporating both reducing and re-bridging functions, is shown to be successful across various proteins.

Delivering potent, stable, targeted and<italic>in vivo</italic>efficacious antibody–drug conjugates (ADCs) using pyridazinedione functional disulfide re-bridging reagents.

Disulfide bridging offers a convenient approach to generate site-selective antibody conjugates from native antibodies. To optimise the reagents available achieve this strategy, we describe here use of dibromomaleimides designed undergo accelerated post-conjugation hydrolysis. Conjugation and hydrolysis, which serve 'lock' as robustly stable maleamic acids, is achieved in just over 1 h. This dramatic acceleration also shown infer significant improvements homogeneity, demonstrated by mass...

Herein we report novel protocols for the generation and application of dibromopyridazinediones, an exciting class disulfide bridging reagents.

In recent years there has been rising interest in the field of protein–protein conjugation, especially related to bispecific antibodies (bsAbs) and their therapeutic applications. These constructs contain two paratopes capable binding distinct epitopes on target molecules are thus able perform complex biological functions (mechanisms action) not available monospecific mAbs. Traditionally these bsAbs have constructed through protein engineering, but recently chemical methods for construction...

Starburst dendrimer, a structurally defined, spherical macromolecule composed of repeating polyamidoamino subunits, was investigated to augment plasmid-mediated gene transfer efficiency in murine cardiac transplantation model. The grafts were directly injected with naked pCH110, plasmid encoding β-galactosidase (β-Gal), or pCH110-dendrimer complex, and reporter expression determined by X-Gal staining. demonstrated widespread extended β-Gal both myocytes the graft infiltrating cells from 7 28...

We develop a facile approach to fabricating multifunctional dendrimer-stabilized gold nanoparticles (Au DSNPs) for cancer cell targeting and imaging. In this work, amine-terminated generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers pre-functionalized with folic acid (FA) fluorescein isothiocyanate (FI) are complexed Au(III) ions, followed by acetylation of the amine groups on dendrimer surfaces. This one-step process leads spontaneous formation 6 nm-sized Au stabilized bearing both...