Poly(vinylpyridine-co-vinylpyridine N-oxide) Excipients Mediate Rapid Dissolution and Sustained Supersaturation of Posaconazole Amorphous Solid Dispersions.

The chemical structure of excipients molecularly mixed in an amorphous solid dispersion (ASD) has a significant impact on properties of the ASD including dissolution behavior, physical stability, and bioavailability. Polymers used in ASDs require a balance between hydrophobic and hydrophilic functionalities to ensure rapid dissolution of the amorphous dispersion as well as sustained supersaturation of the drug in solution. This work demonstrates the use of postpolymerization functionalization of poly(vinylpyridine) excipients to elucidate the impact of polymer properties on the dissolution behavior of amorphous dispersions containing posaconazole. It was found that N-oxidation of pyridine functionalities increased the solubility of poly(vinylpyridine) derivatives in neutral aqueous conditions and allowed for nanoparticle formation which supplied posaconazole into solution at concentrations exceeding those achieved by more conventional excipients such as hydroxypropyl methylcellulose acetate succinate (HPMCAS) or Eudragit E PO. By leveraging these functional modifications of the parent poly(vinylpyridine) excipient to increase polymer hydrophilicity and minimize the effect of polymer on pH, a new polymeric excipient was optimized for rapid dissolution and supersaturation maintenance for a model compound.

Preclinical Characterization of 18F-MK-6240, a Promising PET Tracer for In Vivo Quantification of Human Neurofibrillary Tangles.

A PET tracer is desired to help guide the discovery and development of disease-modifying therapeutics for neurodegenerative diseases characterized by neurofibrillary tangles (NFTs), the predominant tau pathology in Alzheimer disease (AD). We describe the preclinical characterization of the NFT PET tracer 18F-MK-6240. METHODS: In vitro binding studies were conducted with 3H-MK-6240 in tissue slices and homogenates from cognitively normal and AD human brain donors to evaluate tracer affinity and selectivity for NFTs. Immunohistochemistry for phosphorylated tau was performed on human brain slices for comparison with 3H-MK-6240 binding patterns on adjacent brain slices. PET studies were performed with 18F-MK-6240 in monkeys to evaluate tracer kinetics and distribution in the brain. 18F-MK-6240 monkey PET studies were conducted after dosing with unlabeled MK-6240 to evaluate tracer binding selectivity in vivo. RESULTS: The 3H-MK-6240 binding pattern was consistent with the distribution of phosphorylated tau in human AD brain slices. 3H-MK-6240 bound with high affinity to human AD brain cortex homogenates containing abundant NFTs but bound poorly to amyloid plaque-rich, NFT-poor AD brain homogenates. 3H-MK-6240 showed no displaceable binding in the subcortical regions of human AD brain slices and in the hippocampus/entorhinal cortex of non-AD human brain homogenates. In monkey PET studies, 18F-MK-6240 displayed rapid and homogeneous distribution in the brain. The 18F-MK-6240 volume of distribution stabilized rapidly, indicating favorable tracer kinetics. No displaceable binding was observed in self-block studies in rhesus monkeys, which do not natively express NFTs. Moderate defluorination was observed as skull uptake. CONCLUSION: 18F-MK-6240 is a promising PET tracer for the in vivo quantification of NFTs in AD patients.

Discovery of 6-(Fluoro-(18)F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine ([(18)F]-MK-6240): A Positron Emission Tomography (PET) Imaging Agent for Quantification of Neurofibrillary Tangles (NFTs).

Neurofibrillary tangles (NFTs) made up of aggregated tau protein have been identified as the pathologic hallmark of several neurodegenerative diseases including Alzheimer's disease. In vivo detection of NFTs using PET imaging represents a unique opportunity to develop a pharmacodynamic tool to accelerate the discovery of new disease modifying therapeutics targeting tau pathology. Herein, we present the discovery of 6-(fluoro-(18)F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine, 6 ([(18)F]-MK-6240), as a novel PET tracer for detecting NFTs. 6 exhibits high specificity and selectivity for binding to NFTs, with suitable physicochemical properties and in vivo pharmacokinetics.

Coercing bisphosphonates to kill cancer cells with nanoscale coordination polymers.

Nanoscale coordination polymers containing exceptionally high loadings of bisphosphonates were coated with single lipid bilayers to control the drug release kinetics and functionalized with a targeting ligand to endow cell-targeting capability, leading to much enhanced cytotoxicity against human lung and pancreatic cancer cells.

Mesoporous Silica Nanoparticles with Co-Condensed Gadolinium Chelates for Multimodal Imaging.

Several mesoporous silica nanoparticle (MSN) contrast agents have been synthesized using a co-condensation method to incorporate two different Gd3+ complexes at very high loadings (15.5-28.8 wt %). These MSN contrast agents, with an MCM-41 type pore structure, were characterized using a variety of methods including SEM and TEM, nitrogen adsorption measurements, thermogravimetric analysis (TGA), direct current plasma (DCP) spectroscopy, and powder X-ray diffraction (PXRD). The magnetic resonance (MR) relaxivities of these contrast agents were determined using a 3 T MR scanner. The r1 relaxivities of these nanoparticles range from 4.1 to 8.4 mM-1s-1 on a per Gd basis. Additionally, the MSN particles were functionalized with an organic fluorophore and cancer cell targeting peptide to allow for demonstration of both the optical and MR contrast enhancing capabilities in vitro.

Multifunctional mesoporous silica nanospheres with cleavable Gd(III) chelates as MRI contrast agents: synthesis, characterization, target-specificity, and renal clearance.

Mesoporous silica nanospheres (MSNs) are a promising material for magnetic resonance imaging (MRI) contrast agents. In this paper multifunctional MSNs with cleavable Gd(III) chelates are synthesized and characterized, and their applicability as MRI contrast agents is demonstrated both in vitro and in vivo. The MSNs contain Gd(III) chelates that are covalently linked via a redox-responsive disulfide moiety. The MSNs are further functionalized with polyethylene glycol (PEG) and an anisamide ligand to improve their biocompatibility and target specificity. The effectiveness of MSNs as an MRI imaging contrast agent and their targeting ability are successfully demonstrated in vitro using human colon adenocarcinoma and pancreatic cancer cells. Finally, the capability of this platform as an in vivo MRI contrast agent is tested using a 3T scanner. The Gd(III) chelate was quickly cleaved by the blood pool thiols and eliminated through the renal excretion pathway. Further tuning of the Gd(III) chelate release kinetics is needed before the MSN system can be used as target-specific MRI contrast agents in vivo.

Nanoscale metal-organic frameworks for biomedical imaging and drug delivery.

Metal-organic frameworks (MOFs), a class of hybrid materials formed by the self-assembly of polydentate bridging ligands and metal-connecting points, have been studied for a variety of applications. Recently, these materials have been scaled down to nanometer sizes, and this Account details the development of nanoscale metal-organic frameworks (NMOFs) for biomedical applications. NMOFs possess several potential advantages over conventional nanomedicines such as their structural and chemical diversity, their high loading capacity, and their intrinsic biodegradability. Under relatively mild conditions, NMOFs can be obtained as either crystalline or amorphous materials. The particle composition, size, and morphology can be easily tuned to optimize the final particle properties. Researchers have employed two general strategies to deliver active agents using NMOFs: by incorporating active agents into the frameworks or by loading active agents into the pores and channels of the NMOFs. The modification of NMOF surfaces with either silica coatings or organic polymers improves NMOF stability, fine-tunes their properties, and imparts additional functionality. Preliminary biomedical applications of NMOFs have focused on their use as delivery vehicles for imaging contrast agents and molecular therapeutics. Because NMOFs can carry large amounts of paramagnetic metal ions, they have been extensively explored as magnetic resonance imaging (MRI) contrast agents. Both Gd(3+)- and Mn(2+)-containing NMOFs have shown excellent efficacy as T(1)-weighted contrast agents with large per metal- and per particle-based MR relaxivities. Fe(3+)-containing NMOFs have demonstrated excellent T(2)-weighted contrast enhancement. Upon intravenous injection of iron carboxylate NMOFs in Wistar rats, researchers observed negative signal enhancement in the liver and spleen, which dissipated over time, indicating the degradation and clearance of the NMOF. Through the incorporation of luminescent or high Z element building blocks, NMOFs have also served as viable contrast agents for optical imaging or X-ray computed tomography (CT) imaging. Incorporation of membrane impermeable dyes into NMOFs allowed for their uptake by cancer cells and for their controlled release as the framework decomposed. NMOFs have been used to deliver anticancer drugs and other chemotherapeutics. Cisplatin prodrugs were incorporated within NMOFs at exceptionally high levels, either through use of the prodrug as the building block or through attachment of the prodrug onto the framework after synthesis. These NMOFs were encapsulated within a silica shell and targeted to cancer cells. In vitro assays revealed that the targeted NMOFs possessed similar efficacy to cisplatin, while the nontargeted NMOFs were less active. Several different therapeutic molecules were loaded within porous iron-carboxylate NMOFs at unprecedented levels. The NMOF showed sustained drug release with no burst effect, and in vitro assays revealed that the nanoencapsulated drug possessed similar efficacy to the free drug. Although still at a very early stage of development, NMOFs have already shown great promise as a novel platform for nanomedicine. The compositional tunability and mild synthetic conditions used to produce NMOFs should allow for the incorporation of other imaging and therapeutic agents and their effective delivery to targeted cells in vivo.

Hybrid nanomaterials for biomedical applications.

Hybrid nanomaterials, composed of both inorganic and organic components, have recently been examined as promising platforms for imaging and therapeutic applications. This unique class of nanomaterials can not only retain beneficial features of both the inorganic and organic components, but also provides the ability to systematically tune the properties of the hybrid material through the combination of functional components. This feature article will summarize recent advances in the design and synthesis of hybrid nanomaterials and their applications in biological and biomedical areas. The hybrid nanomaterials to be discussed fall into two main categories, silica based materials and nanoscale metal-organic frameworks. Their applications as imaging contrast agents and nanotherapeutics will be highlighted.

Metal-organic frameworks as potential drug carriers.

Nanoparticle-based therapeutics have received increasing attention, as these systems can alleviate many drawbacks of conventional therapy. Metal-organic frameworks (MOFs), a new class of hybrid materials composed of metal ions and organic bridging ligands, have emerged as a promising platform for drug delivery, owing to their high drug loadings, biodegradability, and versatile functionality. The bulk MOF materials can absorb and release large amounts of therapeutics including ibuprofen, procainamide, and nitric oxide. Scale-down of MOFs to the nanoregime yields nanoscale metal-organic frameworks (NMOFs) that are more applicable as delivery vehicles, such as selective delivery of cisplatin prodrugs. Although progress has been made in utilizing NMOFs for drug delivery, many improvements must occur before they can become viable nanotherapeutics.

Postsynthetic modifications of iron-carboxylate nanoscale metal-organic frameworks for imaging and drug delivery.

Fe(III)-carboxylate nanoscale metal-organic frameworks (NMOFs) with the MIL-101 structure were synthesized using a solvothermal technique with microwave heating. The approximately 200 nm particles were characterized using a variety of methods, including SEM, PXRD, nitrogen adsorption measurements, TGA, and EDX. By replacing a percentage of the bridging ligand (terephthalic acid) with 2-amino terephthalic acid, amine groups were incorporated into the framework to provide sites for covalent attachment of biologically relevant cargoes while still maintaining the MIL-101 structure. In proof-of-concept experiments, an optical contrast agent (a BODIPY dye) and an ethoxysuccinato-cisplatin anticancer prodrug were successfully incorporated into the Fe(III)-carboxylate NMOFs via postsynthetic modifications of the as-synthesized particles. These cargoes are released upon the degradation of the NMOF frameworks, and the rate of cargo release was controlled by coating the NMOF particles with a silica shell. Potential utility of the new NMOF-based nanodelivery vehicles for optical imaging and anticancer therapy was demonstrated in vitro using HT-29 human colon adenocarcinoma cells.