Hybrid Nanoparticles for Anticancer Drug Delivery

Nanoparticle-based anticancer has the potential to improve cancer therapy as they generally show greater efficacy with less toxicity than their small molecules counterparts. In this work, the synthesis, characterization, in vitro, and in vivo evaluation of nanoparticle platforms to deliver platinum anticancer drugs are discussed. First, cisplatin-containing co-condensed silica nanoparticles were developed. These nanoparticles could deliver up to 30 wt% cisplatin and could be targeted to cancer cells by the surface attachment of appropriate ligands. The targeted nanoparticles had comparable efficacy to cisplatin in vitro. A new nanoparticle platform, known as polysilsesquioxanes (PSQ) was developed to deliver the platinum anticancer drugs cisplatin and oxaliplatin. These nanoparticles have remarkably high drug loading, up to 47 wt% oxaliplatin and 42 wt% cisplatin, respectively, and can selectively release their cargos in the tumor environment. Both PSQ nanoparticles were functionalized with a polyethylene glycol (PEG) shell. In vivo evaluations against multiple xenograft models of pancreatic or lung cancers demonstrated that PSQ nanoparticles had comparable or better efficacy than oxaliplatin or cisplatin. Further development of all three nanoparticle platforms is ongoing to fully realize their clinical potential.Doctor of Philosoph

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

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 nano-regime yields nanoscale metal-organic frameworks (NMOFs) which 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

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

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 ~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 post-synthetic 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 nano-delivery vehicles for optical imaging and anticancer therapy were demonstrated in vitro using HT-29 human colon adenocarcinoma cells

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

471 Arrhythmia-free survival in early-persistent atrial fibrillation patients undergoing radiofrequency catheter ablation

Abstract Aims Despite advances in success rate of paroxysmal atrial fibrillation (PAF) ablation, outcomes of radiofrequency catheter ablation (RFCA) in patients with persistent AF are highly variable. Early persistent AF (EPsAF) is defined as AF that is sustained beyond 7 days but is less than 3 months in duration. Arrhythmia-free survival data after RFCA in this specific population are still limited. We sought to report the outcomes of RFCA in the subgroup of patients with EPsAF, compared to those with PAF and with 'late' persistent AF (LPsAF) lasting between 3 and 12 months. Methods and results Data from 1143 consecutive AF patients receiving their first RFCA were prospectively collected. Patients with EPsAF (n = 190) were compared with PAF (n = 531) and LPsAF (n = 422) patients. All patients received pulmonary vein antrum isolation + posterior wall and sustained non-pulmonary vein (PV) trigger ablation. Non-sustained non-PV triggers were ablated based on operator discretion. Non-PV triggers were defined as sites of firing leading to sustained (>30 s) or non-sustained arrhythmias (<30 s, including premature atrial contractions ≥10 beats/min) with earliest activation outside the PVs. Mean age of the population was 64 ± 11 years. Female patients were more in PAF group (39%) compared to EPsAF (26%) and LPsAF (28%) (P < 0.001). There was no difference in other clinical characteristics among populations. Non-PV triggers were detected more in EPsAF [127 (66.8%)], and LPsAF [296 (70.1%)] patients compared to PAF [185 (34.8%)] (P < 0.001).One-year arrhythmia-free survival rate after a single procedure was 75.0% (398), 74.2% (141), and 64.5% (272) in PAF, EPsAF, and LPsAF, respectively. Success rate was significantly higher in PAF {[HR: 0.67 (0.53, 0.84), P = 0.001] and EPsAF [HR: 0.67 (0.49, 0.93)], P = 0.015} compared to LPsAF. Conclusions In patients with EPsAF, RFCA may result in significantly better freedom from atrial arrhythmias, compared to LPsAF. In this cohort, ablation might be reasonable as first line approach to improve outcomes and prevent AF progression

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

Long-term Outcome of Pulmonary Vein Isolation Versus Amiodarone Therapy in Patients with Coexistent Persistent AF and Congestive Heart Failure

Although pharmacological rhythm control of AF in patients with heart failure with reduced ejection fraction (HFrEF) does not seem to provide any benefit over rate control, catheter ablation of AF has been shown to improve clinical outcomes. These results can be explained with higher success rates of catheter ablation in restoring and maintaining sinus rhythm compared with antiarrhythmic drugs. In addition, pharmacotherapy is not void of side-effects, which are thought to offset its potential antiarrhythmic benefits. Therefore, efforts should be made towards optimisation of ablation techniques for AF in patients with HFrEF