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A growing number of nanomedicines entered the clinical trials and improved our understanding of the in vivo responses expected in humans. The in vitro drug release represents an important critical quality attribute involved in pharmacokinetics. Establishing in vitro-in vivo relationships for nanomedicines requires a careful analysis of the clinical data with respect to the unique differences between drugs and nanomedicines. Also, the biorelevant assay must reflect the release mechanism of the carrier. Four drug delivery systems of doxorubicin were evaluated for their in vitro release behavior under biorelevant conditions using the dispersion releaser. The pharmacokinetics observed during the first-in-men clinical trials were analyzed using a custom-made physiologically-based nanocarrier biopharmaceutics model. The drug product Lipodox® and the clinical candidate NanoCore-7.4 were evaluated to validate the model. Afterward, the in vivo performances of the preclinical candidates NanoCore-6.4 and doxorubicin-loaded nano-cellular vesicle technology systems (an extracellular vesicle preparation) were predicted. In vitro and in vivo release were in good correlation as indicated by the coefficients of determination of 0.98648 (NanoCore-7.4) and 0.94107 (Lipodox®). The predictions required an estimation of the carrier half-life in blood circulation leading to considerable uncertainty. Still, the simulations narrow down the possible scenarios in the clinical evaluation of nanomedicines and provide a valuable addition to animal studies.

For many years, nanomedicine is pushing the boundaries of drug delivery. When applying these novel therapeutics, safety considerations are not only a key concern when entering clinical trials but also an important decision point in product development. Standing at the crossroads, nanomedicine may be able to escape the niche markets and achieve wider acceptance by the pharmaceutical industry. While there is a new generation of drug delivery systems, the extracellular vesicles, standing on the starting line, unresolved issues and new challenges emerge from their translation from bench to bedside. Some key features of injectable nanomedicines contribute to the predictability of the pharmacological and toxicological effects. So far, only a few of the physicochemical attributes of nanomedicines can be justified by a direct mathematical relationship between the in vitro and the in vivo responses. To further develop extracellular vesicles as drug carriers, we have to learn from more than 40 years of clinical experience in liposomal delivery and pass on this knowledge to the next generation. Our quick guide discusses relationships between physicochemical characteristics and the in vivo response, commonly referred to as in vitro-in vivo correlation. Further, we highlight the key role of computational methods, lay open current knowledge gaps, and question the established design strategies. Has the recent progress improved the predictability of targeted delivery or do we need another change in perspective?

Introduction: Adverse left ventricle remodeling can be measured as a reduction in ejection fraction after myocardial infarction. Left ventricle remodeling leads to congestive heart failure and is a main determinant of mortality and morbidity after myocardial infarction. Berberine is an isoquinoline alkaloid extracted from barberry that has anti-inflammatory and anti-oxidant activities. Pretreatment with long-term administration of high doses of berberine has shown beneficial effects in experimental diabetes and cardiac ischemia reperfusion injury. However, the poor solubility and the short half-life in the circulation have impeded the clinical use of berberine. Purpose: To examine whether encapsulation of berberine into long-circulating liposomes could improve its therapeutic availability and efficacy to protect cardiac function in vivo. Methods: Berberine was loaded into liposomes at a concentration of 0.3 mg/ml. Lipopolysaccharide (LPS) activated mouse macrophages RAW 264.7 were treated with free berberine or liposome-encapsulated berberine (Lipo-Berb) and analyzed for cell viability, reactive oxygen species production and cytokine secretion. C57BL/6J male mice (10-12 week old) subjected to myocardial infarction (MI) via permanent ligation of the left anterior descending artery were blindly selected for intravenous injection of empty liposomes, free berberine or lipo-Berb (1.5 mg/kg). Three doses were administered at the onset of MI, and at 3 and 6 days after MI. Ejection fraction was assessed by echocardiography at baseline, 7 and 28 days after MI. Results: Free berberine improved the viability of LPS-insulted macrophages, reduced production of reactive oxygen species and inhibited the secretion of inflammatory mediators including IL-6 and TNFα. As expected these protective effects of berberine in vitro were diminished upon encapsulation into liposomes. In vivo, however, the liposome-encapsulated berberine significantly preserved ejection fraction after 28 days of MI while free berberine did not show any preservation of ejection fraction (29.5±1.9 for lipo-Berb, 18.2±3.2 for free berberine and 18.0±3.1 for empty liposomes; n=6-10; p

Introduction: Adverse left ventricle remodeling can be measured as a reduction in ejection fraction after myocardial infarction. Left ventricle remodeling leads to congestive heart failure and is a main determinant of mortality and morbidity after myocardial infarction. Berberine is an isoquinoline alkaloid extracted from barberry that has anti-inflammatory and anti-oxidant activities. Pretreatment with long-term administration of high doses of berberine has shown beneficial effects in experimental diabetes and cardiac ischemia reperfusion injury. However, the poor solubility and the short half-life in the circulation have impeded the clinical use of berberine. Purpose: To examine whether encapsulation of berberine into long-circulating liposomes could improve its therapeutic availability and efficacy to protect cardiac function in vivo. Methods: Berberine was loaded into liposomes at a concentration of 0.3 mg/ml. Lipopolysaccharide (LPS) activated mouse macrophages RAW 264.7 were treated with free berberine or liposome-encapsulated berberine (Lipo-Berb) and analyzed for cell viability, reactive oxygen species production and cytokine secretion. C57BL/6J male mice (10-12 week old) subjected to myocardial infarction (MI) via permanent ligation of the left anterior descending artery were blindly selected for intravenous injection of empty liposomes, free berberine or lipo-Berb (1.5 mg/kg). Three doses were administered at the onset of MI, and at 3 and 6 days after MI. Ejection fraction was assessed by echocardiography at baseline, 7 and 28 days after MI. Results: Free berberine improved the viability of LPS-insulted macrophages, reduced production of reactive oxygen species and inhibited the secretion of inflammatory mediators including IL-6 and TNFα. As expected these protective effects of berberine in vitro were diminished upon encapsulation into liposomes. In vivo, however, the liposome-encapsulated berberine significantly preserved ejection fraction after 28 days of MI while free berberine did not show any preservation of ejection fraction (29.5±1.9 for lipo-Berb, 18.2±3.2 for free berberine and 18.0±3.1 for empty liposomes; n=6-10; p

Adenosine is an ubiquitous local modulator that regulates various physiological and pathological functions by stimulating four membrane receptors, namely A1, A2A, A2B, and A3. Among these G protein-coupled receptors, the A3 subtype is found mainly in the lung, liver, heart, eyes, and brain in our body. It has been associated with cerebroprotection and cardioprotection, as well as modulation of cellular growth upon its selective activation. On the other hand, its inhibition by selective antagonists has been reported to be potentially useful in the treatment of pathological conditions including glaucoma, inflammatory diseases, and cancer.

Some pyrazolotriazolopyrimidines bearing different heteroarylcarbamoylamino moieties at the N5-position are described. We previously reported the synthesis of a water soluble compound with high potency and selectivity versus the human A3 adenosine receptor as antagonist, and herein we present an enlarged series of compounds related to the previously mentioned one. These compounds showed A3 adenosine receptor affinity in the nanomolar range and different levels of selectivity evaluated in radioligand binding assays at human A1, A2A, A2B, and A3 adenosine receptors. In particular, the effect of the heteroaryl substituents at the N5 position has been analyzed. This study allows us to recognize that the presence of a pyridinium moiety in this position not only increases water solubility but also improves or retains potency and selectivity at the human A3 adenosine receptors. In contrast, replacement of pyridine with different heterocycles produces loss of affinity and selectivity at the human A3 adenosine receptors. A molecular modeling study has been carried out with the aim to explain these various binding profiles.

A combined target-based and ligand-based drug design approach has been carried out to define a novel pharmacophore model of the human A3 receptor antagonists. High throughput molecular docking and comparative molecular field analysis (CoMFA) have been used in tandem to assemble a new target based pharmacophore model.

A new, highly potent, selective, and water-soluble antagonist of the hA3 adenosine receptor was synthesized and tested in binding and functional assays. Compound 4 (5-[[(4- pyridyl)amino]carbonyl]amino-8-methyl-2-(2-furyl)-pyrazolo- [4,3-e]1,2,4-triazolo[1,5-c]pyrimidine hydrochloride) displayed high water solubility (15 mM) and the highest affinity (Ki ) 0.01 nM) and selectivity for the hA3 versus A1, A2A, and A2B receptors (>10000-fold) ever reported. A Schild analysis of the antagonism by 4 of agonist-induced inhibition of cAMP production in CHO cells expressing the hA3 receptor indicated a KB value of 0.20 nM.