Lung-to-Heart Nano-in-Micro Peptide Promotes Cardiac Recovery in a Pig Model of Chronic Heart Failure.

BACKGROUND: The lack of disease-modifying drugs is one of the major unmet needs in patients with heart failure (HF). Peptides are highly selective molecules with the potential to act directly on cardiomyocytes. However, a strategy for effective delivery of therapeutics to the heart is lacking. OBJECTIVES: In this study, the authors sought to assess tolerability and efficacy of an inhalable lung-to-heart nano-in-micro technology (LungToHeartNIM) for cardiac-specific targeting of a mimetic peptide (MP), a first-in-class for modulating impaired L-type calcium channel (LTCC) trafficking, in a clinically relevant porcine model of HF. METHODS: Heart failure with reduced ejection fraction (HFrEF) was induced in Göttingen minipigs by means of tachypacing over 6 weeks. In a setting of overt HFrEF (left ventricular ejection fraction [LVEF] 30% ± 8%), animals were randomized and treatment was started after 4 weeks of tachypacing. HFrEF animals inhaled either a dry powder composed of mannitol-based microparticles embedding biocompatible MP-loaded calcium phosphate nanoparticles (dpCaP-MP) or the LungToHeartNIM only (dpCaP without MP). Efficacy was evaluated with the use of echocardiography, invasive hemodynamics, and biomarker assessment. RESULTS: DpCaP-MP inhalation restored systolic function, as shown by an absolute LVEF increase over the treatment period of 17% ± 6%, while reversing cardiac remodeling and reducing pulmonary congestion. The effect was recapitulated ex vivo in cardiac myofibrils from treated HF animals. The treatment was well tolerated, and no adverse events occurred. CONCLUSIONS: The overall tolerability of LungToHeartNIM along with the beneficial effects of the LTCC modulator point toward a game-changing treatment for HFrEF patients, also demonstrating the effective delivery of a therapeutic peptide to the diseased heart.

Silica-Coated Nanoparticles with a Core of Zinc, l-Arginine, and a Peptide Designed for Oral Delivery.

Nanoparticle constructs for oral peptide delivery at a minimum must protect and present the peptide at the small intestinal epithelium in order to achieve oral bioavailability. In a reproducible, scalable, surfactant-free process, a core was formed with insulin in ratios with two established excipients and stabilizers, zinc chloride and l-arginine. Cross-linking was achieved with silica, which formed an outer shell. The process was reproducible across several batches, and physicochemical characterization of a single batch was confirmed in two independent laboratories. The silica-coated nanoparticles (SiNPs) entrapped insulin with high entrapment efficiency, preserved its structure, and released it at a pH value present in the small intestine. The SiNP delivered insulin to the circulation and reduced plasma glucose in a rat jejunal instillation model. The delivery mechanism required residual l-arginine in the particle to act as a permeation enhancer for SiNP-released insulin in the jejunum. The synthetic process was varied in terms of ratios of zinc chloride and l-arginine in the core to entrap the glucagon-like peptide 1 analogue, exenatide, and bovine serum albumin. SiNP-delivered exenatide was also bioactive in mice to some extent following oral gavage. The process is the basis for a platform for oral peptide and protein delivery.

Physicochemical, pharmacokinetic and pharmacodynamic analyses of amphiphilic cyclodextrin-based nanoparticles designed to enhance intestinal delivery of insulin.

Due to excellent efficacy, low toxicity, and well-defined selectivity, development of new injectable peptides is increasing. However, the translation of these drugs into products for effective oral delivery has been restricted due to poor oral bioavailability. Nanoparticle (NP) formulations have potential to overcome the barriers to oral peptide delivery through protecting the payload and increasing bioavailability. This study describes the rational design, optimization and evaluation of a cyclodextrin-based NP entrapping insulin glulisine for intestinal administration. A cationic amphiphilic cyclodextrin (click propyl-amine cyclodextrin (CD)) was selected as the primary complexing agent for NP development. Following NP synthesis, in vitro characterization was performed. The insulin glulisine NPs exhibited an average size of 109 ±â€¯9 nm, low polydispersity index (0.272) negative zeta potential (-25 ±â€¯3 mV), high association efficiency (71.4 ±â€¯3.37%) and an insulin loading of 10.2%. In addition, the NPs exhibited colloidal stability in intestinal-biorelevant media (SIF, supplemented-SIF 1% (w/v) and FaSSIF-V2) for up to 4 h. Proteolysis studies indicated that the NPs conferred protection to the entrapped insulin relative to free insulin. In vivo rat jejunal instillation studies demonstrated that the NPs mediated systemic insulin absorption, accompanied by a decrease in blood glucose levels. The relative bioavailability of the instilled insulin (50 IU/kg) from the NP was 5.5% compared to subcutaneous administration of insulin solution (1 IU/kg). The pharmacodynamic and pharmacokinetic data indicate that this cyclodextrin-based formulation may have potential for further research as an oral insulin dosage form.

Building the design, translation and development principles of polymeric nanomedicines using the case of clinically advanced poly(lactide(glycolide))-poly(ethylene glycol) nanotechnology as a model: An industrial viewpoint.

The design of the first polymeric nanoparticles could be traced back to the 1970s, and has thereafter received considerable attention, as evidenced by the significant increase of the number of articles and patents in this area. This review article is an attempt to take advantage of the existing literature on the clinically tested and commercialized biodegradable PLA(G)A-PEG nanotechnology as a model to propose quality building and outline translation and development principles for polymeric nano-medicines. We built such an approach from various building blocks including material design, nano-assembly - i.e. physicochemistry of drug/nano-object association in the pharmaceutical process, and release in relevant biological environment - characterization and identification of the quality attributes related to the biopharmaceutical properties. More specifically, as envisaged in a translational approach, the reported data on PLA(G)A-PEG nanotechnology have been structured into packages to evidence the links between the structure, physicochemical properties, and the in vitro and in vivo performances of the nanoparticles. The integration of these bodies of knowledge to build the CMC (Chemistry Manufacturing and Controls) quality management strategy and finally support the translation to proof of concept in human, and anticipation of the industrialization takes into account the specific requirements and biopharmaceutical features attached to the administration route. From this approach, some gaps are identified for the industrial development of such nanotechnology-based products, and the expected improvements are discussed. The viewpoint provided in this article is expected to shed light on design, translation and pharmaceutical development to realize their full potential for future clinical applications.

Oral delivery of diabetes peptides - Comparing standard formulations incorporating functional excipients and nanotechnologies in the translational context.

While some orally delivered diabetes peptides are moving to late development with standard formulations incorporating functional excipients, the demonstration of the value of nanotechnology in clinic is still at an early stage. The goal of this review is to compare these two drug delivery approaches from a physico-chemical and a biopharmaceutical standpoint in an attempt to define how nanotechnology-based products can be differentiated from standard oral dosage forms for oral bioavailability of diabetes peptides. Points to consider in a translational approach are outlined to seize the opportunities offered by a better understanding of both the intestinal barrier and of nano-carriers designed for oral delivery.

Drug delivery design for intravenous route with integrated physicochemistry, pharmacokinetics and pharmacodynamics: illustration with the case of taxane therapeutics.

This review is aimed at combining the published data on taxane formulations into a generalized Drug Delivery approach, starting from the physicochemistry and assessing its relationships with the pharmacokinetics, the biodistribution and the pharmacodynamics. Owing to the number and variety of taxane formulation designs, we considered this class of cytotoxic anticancer agents of particular interest to illustrate the concepts attached to this approach. According to the history of taxane development, we propose a classification as (i) "surfactant-based formulations" first generation, (ii) "surfactant-free formulations" second generation and (iii) "modulated pharmacokinetics drug delivery systems" third generation. Since our objective was to make the link between (i) the physicochemistry of the drug and carrier and (ii) the efficacy and safety of the drug in preclinical animal models and (iii) in human, we focused on the drug delivery technologies that were tested in clinic.