In vitro and in vivo pharmacokinetic characterization, chiral conversion and PBPK scaling towards human PK simulation of S-MRI-1867, a drug candidate for Hermansky-Pudlak syndrome pulmonary fibrosis.

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder that affects lysosome-related organelles, often leading to fatal pulmonary fibrosis (PF). The search for a treatment for HPS pulmonary fibrosis (HPSPF) is ongoing. S-MRI-1867, a dual cannabinoid receptor 1 (CB1R)/inducible nitric oxide synthase (iNOS) inhibitor, has shown great promise for the treatment of several fibrotic diseases, including HPSPF. In this study, we investigated the in vitro ADME characteristics of S-MRI-1867, as well as its pharmacokinetic (PK) properties in mice, rats, dogs, and monkeys. S-MRI-1867 showed low aqueous solubility (< 1 µg/mL), high plasma protein binding (>99%), and moderate to high metabolic stability. In its preclinical PK studies, S-MRI-1867 exhibited moderate to low plasma clearance (CLp) and high steady-state volume of distribution (Vdss) across all species. Despite the low solubility and P-gp efflux, S-MRI-1867 showed great permeability and metabolic stability leading to a moderate bioavailability (21-60%) across mouse, rat, dog, and monkey. Since the R form of MRI-1867 is CB1R-inactive, we investigated the potential conversion of S-MRI-1867 to R-MRI-1867 in mice and found that the chiral conversion was negligible. Furthermore, we developed and validated a PBPK model that adequately fits the PK profiles of S-MRI-1867 in mice, rats, dogs, and monkeys using various dosing regimens. We employed this PBPK model to simulate the human PK profiles of S-MRI-1867, enabling us to inform human dose selection and support the advancement of this promising drug candidate in the treatment of HPSPF.

Polymeric micelles for oral drug delivery.

In the case of chronic therapies, the oral route is often the preferred route for drug administration given its acceptability and convenience. However, various factors which limit drug absorption through the gastro-intestinal (GI) mucosa contribute to restricting the bioavailability of the drug, that is, the actual amount which reaches the bloodstream. Among these factors, poor drug permeability through the GI mucosa and/or low aqueous solubility are of central importance. Polymeric micelles, which form upon self-assembly of amphiphilic macromolecules, can act as vehicles for the oral delivery of these drugs. This manuscript summarizes the literature in relation to the design of these micellar systems and their characterization with respect to drug loading and retention properties as well as the ability to withstand dissociation and drug discharge upon oral administration. Also, the role of certain polymers in improving drug absorption through the GI mucosa, either by increasing membrane permeability to the drug and/or carrier or by inhibiting drug efflux transporters in the GI mucosa, is discussed. Finally, this review reports other drug delivery strategies such as using bioadhesive polymers which may lengthen residence time in the GI tract and promote drug permeation, or rendering the polymeric micelles pH-sensitive in order to ensure drug release from the carrier at its site of absorption.

Polyester-based micelles and nanoparticles for the parenteral delivery of taxanes.

Taxanes are potent antimitotic agents that have demonstrated efficacy in a wide range of malignancies. Due to their poor water-solubility, these cytostatic drugs were first formulated with low molecular weight surfactants, e.g. Cremophor EL (CrEL) and Tween 80 (polysorbate 80), which are known to exhibit serious adverse effects in humans. In recent years, there has been growing interest in the design of more biocompatible formulations for both paclitaxel and docetaxel. Polymer-based drug carriers represent an attractive venue given the diversity in the array of existing polymers. Most notably, biopolyesters are vastly employed in the field of biomedical research given their biocompatibility and biodegradability. Polyester-based micelles and nanoparticles have been applied to the parenteral delivery of taxanes with varying degrees of success. Block copolymer micelles possess a unique core-shell structure generated through the self-assembly of amphiphilic copolymers in aqueous media. Although these systems have shown greatly enhanced tolerability compared to formulations based on low molecular weight surfactants, in some cases their failure to retain their cargo following parenteral administration has hindered their capacity to target taxanes to solid tumours. While polyester-based nanoparticles possess comparatively greater stability and drug targeting capacity, they frequently display a significant burst effect whereby a major portion of the cargo is immediately discarded from the carrier upon injection. This review focuses on the current application of polyester-based micelles and nanoparticles to the tumour targeting of taxanes. The preparation, loading efficiencies, release kinetics, cytotoxicity and in vivo behaviour of these systems is discussed in detail.

Effect of poly(N-vinyl-pyrrolidone)-block-poly(D,L-lactide) as coating agent on the opsonization, phagocytosis, and pharmacokinetics of biodegradable nanoparticles.

The effect of the coating polymer poly(N-vinyl-pyrrolidone) (PVP) on the protein adsorption, phagocytosis, and pharmacokinetics of poly(D,L-lactide)-based nanoparticles was evaluated in vitro and in vivo. Control poly(ethylene glycol) (PEG)-coated nanoparticles were included for comparison. While no difference between PEG- and PVP-decorated nanoparticles in terms of amount of adsorbed protein was evident upon incubation in single protein solutions (BSA, IgG), incubation in serum revealed a protein adsorption pattern both quantitatively and qualitatively distinct. Larger amounts of complement components and immunoglobulins were found to adhere to PVP-coated particles, whereas PEG particles showed preferential adsorption of apolipoproteins. Furthermore, preopsonization in fresh rather than heat-inactivated serum enhanced uptake of both types of particles by murine RAW 264.7 macrophages. However, when isolated rat Kupffer cells were employed, activation of the complement system significantly enhanced the uptake of PVP-coated nanoparticles compared to PEG particles. Ultimately, PVP-coated nanoparticles exhibited considerably shorter circulation times compared to their PEG counterparts when administered intravenously to rats.

Poly(N-vinyl-pyrrolidone)-block-poly(D,L-lactide) as polymeric emulsifier for the preparation of biodegradable nanoparticles.

Poly(D,L-lactide) (PDLLA) amphiphilic block copolymers were employed as emulsifiers in the preparation of PDLLA nanoparticles by an oil/water emulsion solvent evaporation technique. The surface-active properties of poly(N-vinyl-pyrrolidone)-block-poly(D,L-lactide) (PVP-b-PDLLA) toward the biphasic system were compared to those of polyethylene glycol(PEG)-b-PDLLA of similar composition. PVP-b-PDLLA was found to be a suitable emulsifier for dichloromethane/water emulsions, yielding narrowly distributed nanoparticles (<250 nm) surrounded by a hydrophilic PVP corona. PEG-b-PDLLA, however, was only effective in producing appropriately sized nanoparticles when dichloromethane was replaced with ethyl acetate. Furthermore, the lyoprotectant properties of PVP allowed the freeze-dried nanoparticles to recover their initial size following reconstitution, while PEG-coated nanoparticles could not be redispersed following lyophilization. Two poorly water-soluble drugs, that is, paclitaxel and etoposide, were efficiently loaded into PVP-decorated PDLLA nanoparticles. The entrapment efficiency of etoposide was significantly enhanced by adding MgCl2 to the aqueous phase. It was found that the nanoparticles released the drugs progressively over several days in vitro. The obtained experimental results were corroborated with the theoretical compatibility between a given drug, polymer, and solvent, predicted by total solubility parameters.

Block copolymer micelles: preparation, characterization and application in drug delivery.

Block copolymer micelles are generally formed by the self-assembly of either amphiphilic or oppositely charged copolymers in aqueous medium. The hydrophilic and hydrophobic blocks form the corona and the core of the micelles, respectively. The presence of a nonionic water-soluble shell as well as the scale (10-100 nm) of polymeric micelles are expected to restrict their uptake by the mononuclear phagocyte system and allow for passive targeting of cancerous or inflamed tissues through the enhanced permeation and retention effect. Research in the field has been increasingly focused on achieving enhanced stability of the micellar assembly, prolonged circulation times and controlled release of the drug for optimal targeting. With that in mind, our group has developed a range of block copolymers for various applications, including amphiphilic micelles for passive targeting of chemotherapeutic agents and environment-sensitive micelles for the oral delivery of poorly bioavailable compounds. Here, we propose to review the innovations in block copolymer synthesis, polymeric micelle preparation and characterization, as well as the relevance of these developments to the field of biomedical research.

Stereocomplex block copolymer micelles: core-shell nanostructures with enhanced stability.

Monodisperse stereocomplex block copolymer micelles were obtained through the self-assembly of equimolar mixtures of poly(ethylene glycol)-block-poly(l-lactide) and poly(ethylene glycol)-block-poly(d-lactide) in water. These micelles possessed partially crystallized cores and mean hydrodynamic diameters ranging from 31 to 56 nm, depending on the lactide content. They exhibited kinetic stability and redispersion properties superior to micelles prepared with isotactic or racemic polymers alone. This study demonstrates the advantages of stereocomplex formation in the design of stabilized water-soluble nanoparticles.

Common human UGT1A polymorphisms and the altered metabolism of irinotecan active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38).

7-Ethyl-10-hydroxycamptothecin (SN-38) is the pharmacologically active metabolite of irinotecan, in addition to being responsible for severe toxicity. Glucuronidation is the main metabolic pathway of SN-38 and has been shown to protect against irinotecan-induced gastrointestinal toxicity. The purpose of this study was to determine whether common polymorphic UDP-glucuronosyltransferase (UGT) affects SN-38 glucuronidation. First, kinetic characterization of SN-38-glucuronide (SN-38-G) formation was assessed for all known human UGT1A and UGT2B overexpressed in human embryonic kidney 293 cells. To assess the relative activity of UGT isoenzymes for SN-38, rates of formation of SN-38-G were monitored by liquid chromatography/mass spectrometry analysis and normalized by level of UGT cellular expression. Determination of intrinsic clearances predicts that hepatic UGT1A1 and UGT1A9 and the extrahepatic UGT1A7 are major components in SN-38-G formation, whereas a minor role is suggested for UGT1A6, UGT1A8, and UGT1A10. In support of the involvement of UGT1A9, a strong coefficient of correlation was observed in the glucuronidation of SN-38 and a substrate, mainly glucuronidate, by UGT1A9 (flavopiridol) by human liver microsomes (coefficient of correlation, 0.905; p = 0.002). In vitro functional experiments revealed a negative impact of the UGT1A1 allelic variants. Residual activities of 49, 7, 8, and 11% were observed for UGT1A1*6 (G(71)R), UGT1A1*27 (P(229)Q), UGT1A1*35 (L(233)R), and UGT1A1*7 (Y(486)D), respectively. Common variants of UGT1A7, UGT1A7*3 (N(129)K;R(131)K;W(208)R), and UGT1A7*4 (W(208)R), displayed residual activities of 41 and 28% compared with the UGT1A7*1 allele. Taken together, these data provide the evidence that molecular determinants of irinotecan response may include the UGT1A polymorphisms studied herein and common genetic variants of the hepatic UGT1A9 isoenzyme yet to be described.