Metal Organic Frameworks in Biomedicine Patricia Horcajada,* Ruxandra Gref, Tarek Baati, Phoebe K. Allan, Guillaume Maurin, Patrick Couvreur, G erard F erey, Russell E. Morris, and Christian Serre* Institut Lavoisier, UMR CNRS 8180, Universit e de Versailles St-Quentin en Yvelines, 45 Avenue des Etats-Unis, 78035 Versailles Cedex, France Facult e de Pharmacie, UMR CNRS 8612, Universit e Paris-Sud, 92296 Châtenay-Malabry Cedex, France Institut Charles Gerhardt Montpellier, UMR CNRS 5253, Universit e Montpellier 2, 34095 Montpellier cedex 05, France EaStChem School of Chemistry, University of St. Andrews Purdie Building, St Andrews, KY16 9ST U.K.

Metal-organic frameworks in biomedicine.

The clinical use of anthracyclines like doxorubicin and daunorubicin can be viewed as a sort of double-edged sword. On the one hand, anthracyclines play an undisputed key role in the treatment of many neoplastic diseases; on the other hand, chronic administration of anthracyclines induces cardiomyopathy and congestive heart failure usually refractory to common medications. Second-generation analogs like epirubicin or idarubicin exhibit improvements in their therapeutic index, but the risk of inducing cardiomyopathy is not abated. It is because of their janus behavior (activity in tumors vis-a-vis toxicity in cardiomyocytes) that anthracyclines continue to attract the interest of preclinical and clinical investigations despite their longer-than-40-year record of longevity. Here we review recent progresses that may serve as a framework for reappraising the activity and toxicity of anthracyclines on basic and clinical pharmacology grounds. We review 1) new aspects of anthracycline-induced DNA damage in cancer cells; 2) the role of iron and free radicals as causative factors of apoptosis or other forms of cardiac damage; 3) molecular mechanisms of cardiotoxic synergism between anthracyclines and other anticancer agents; 4) the pharmacologic rationale and clinical recommendations for using cardioprotectants while not interfering with tumor response; 5) the development of tumor-targeted anthracycline formulations; and 6) the designing of third-generation analogs and their assessment in preclinical or clinical settings. An overview of these issues confirms that anthracyclines remain "evergreen" drugs with broad clinical indications but have still an improvable therapeutic index.

/pdf/anthracyclines-molecular-advances-and-pharmacologic-4vygbx1i0b.pdf

Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity

The ferritins: molecular properties, iron storage function and cellular regulation☆

Background The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first broke out in 2019 and subsequently spread worldwide. Chloroquine has been sporadically used in treating SARS-CoV-2 infection. Hydroxychloroquine shares the same mechanism of action as chloroquine, but its more tolerable safety profile makes it the preferred drug to treat malaria and autoimmune conditions. We propose that the immunomodulatory effect of hydroxychloroquine also may be useful in controlling the cytokine storm that occurs late phase in critically ill patients with SARS-CoV-2. Currently, there is no evidence to support the use of hydroxychloroquine in SARS-CoV-2 infection. Methods The pharmacological activity of chloroquine and hydroxychloroquine was tested using SARS-CoV-2-infected Vero cells. Physiologically based pharmacokinetic (PBPK) models were implemented for both drugs separately by integrating their in vitro data. Using the PBPK models, hydroxychloroquine concentrations in lung fluid were simulated under 5 different dosing regimens to explore the most effective regimen while considering the drug's safety profile. Results Hydroxychloroquine (EC50 = 0.72 μM) was found to be more potent than chloroquine (EC50 = 5.47 μM) in vitro. Based on PBPK models results, a loading dose of 400 mg twice daily of hydroxychloroquine sulfate given orally, followed by a maintenance dose of 200 mg given twice daily for 4 days is recommended for SARS-CoV-2 infection, as it reached 3 times the potency of chloroquine phosphate when given 500 mg twice daily 5 days in advance. Conclusions Hydroxychloroquine was found to be more potent than chloroquine to inhibit SARS-CoV-2 in vitro.

In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).

Objectives The frontline drug doxorubicin has been used for treating cancer for over 30 years. While providing a cure in select cases, doxorubicin causes toxicity to most major organs, especially life-threatening cardiotoxicity, which forces the treatment to become dose-limiting.

Key findings  Doxorubicin is known to bind to DNA-associated enzymes, intercalate with DNA base pairs, and target multiple molecular targets to produce a range of cytotoxic effects. For instance, it causes the activation of various molecular signals from AMPK (AMP-activated protein kinase inducing apoptosis) to influence the Bcl-2/Bax apoptosis pathway. By altering the Bcl-2/Bax ratio, downstream activation of different caspases can occur resulting in apoptosis. Doxorubicin also induces apoptosis and necrosis in healthy tissue causing toxicity in the brain, liver, kidney and heart. Over the years, many studies have been conducted to devise a drug delivery system that would eliminate these adverse affects including liposomes, hydrogel and nanoparticulate systems, and we highlight the pros and cons of these drug delivery systems.

Summary  Overall the future for the continued use of doxorubicin clinically against cancer looks set to be prolonged, provided certain enhancements as listed above are made to its chemistry, delivery and toxicity. Increased efficacy depends on these three aims being met satisfactorily as discussed in turn in this review.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.2042-7158.2012.01567.x

Doxorubicin: an update on anticancer molecular action, toxicity and novel drug delivery systems

Daunorubicin (DNR) has been conjugated to succinylated serum albumin by an amide bond joining the amino group of the drug and a carboxyl side chain of the protein either directly or with the intercalation of a peptide spacer arm varying from one to four amino acids. During in vitro incubation with lysosomal hydrolases, intact DNR could be released extensively only from conjugates prepared with a tri- or tetrapeptide spacer arm. These latter conjugates remained very stable in the presence of serum. When tested in vivo against the intraperitoneal form of L1210 leukemia, the conjugates in which DNR was linked to serum albumin directly or via one amino acid were completely inactive but the conjugate with a dipeptide spacer arm was not more active than free DNR. In parallel with the in vitro studies, the best therapeutic results were obtained with the conjugates formed with tri- and tetrapeptidic spacer arms; they were much more active than DNR, inducing a high percentage of long-term survivors. Thus, use of a tri- or tetrapeptide spacer arm is essential to obtain DNR-protein conjugates that remain stable in serum and from which DNR can be released through the action of lysosomal hydrolases. The in vivo results suggest, moreover, that these conjugates are endocytosed by L1210 cells and that DNR is released intracellularly after digestion by lysosomal enzymes. This conjugation method can be applied to other drugs possessing a free amino group and to various potential carriers, such as antibodies, polypeptide hormones, and glycoproteins, that have amino or carboxyl side chains.

https://www.pnas.org/content/pnas/79/2/626.full.pdf

A covalent linkage between daunorubicin and proteins that is stable in serum and reversible by lysosomal hydrolases, as required for a lysosomotropic drug-carrier conjugate: in vitro and in vivo studies.

WHEN a drug can pass freely across cell membranes, it becomes distributed throughout the body fluids whichever its route of administration and invades all cells by diffusion at comparable rates. But if it is firmly associated with a non-permeant, pino-cytizable and digestible carrier, it will tend to remain confined within a smaller fluid space determined by its route of administration, its excretion will be slow and its intracellular penetration will be restricted to the endocytic route (Fig. 1). Free drug will then appear first within lysosomes, following digestion of the carrier. From the lysosomes it will diffuse into the other parts of the cells and eventually into the extracellular fluids. The intracellular concentration of the drug thus becomes dependent on the pinocytic activity of the cells and on the digestive potential of their lysosomes and must exceed the extracellular concentration in the most active cells. Obviously, this model requires the complex to be stable in the body fluids and to dissociate inside lysosomes. The drug itself must be resistant to lysosomal inactivation.

Chemotherapy through lysosomes with a DNA-daunorubicin complex.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/0014-5793%2877%2980717-5

Nanocapsules: A new type of lysosomotropic carrier

The uptake and intracellular accumulation of aminoglycoside antibiotics in lysosomes of cultured rat fibroblasts.

Cultured rat embryo fibroblasts were first allowed to store for 24 h fluorescein-labeled goat immunoglobulins directed against rabbit immunoglobulins (F anti-R IgG), and were subsequently exposed for 24 h to [(3)H]acetylated rabbit immunoglobulins known to bind to the cell membrane either specifically (anti-plasma membrane IgG: A anti-PM IgG) or unspecifically (contol IgG: AC IgG). As a result of immunological interaction between the two antibodies (no effect was found if the cells had been preloaded with control goat FC IgG), a substantial portion of the stored F anti-R IgG was unloaded from its intracellular storage site, appearing in the medium in the form of soluble immune complexes with rabbit A IgG. Part of the unloaded F anti-R IgG also was recovered in association with the plasma membrane, but only when A anti-PM IgG was used. In addition, significant reverse translocation of AC IgG from plasma membrane to lysosomes or some related intracellular storage compartment was also observed. With A anti-PM IgG, this translocation was less marked and affecte at the same time the plasma membrane marker 5'- nucleotidase. Cells that had stored horseradish peroxidase (HRP) simultaneously with F anti-R IgG did not unload HRP when exposed to A anti-PM IgG.

These results support strongly, though not unequivocally, the concept that plasma membrane patches interiorized by endocytosis are recycled, or shuttled, back to the cell surface. In the framework of this concept, recycling antibody-coated membrane is taken to serve as vehicle for the selective intracellular capture and extracellular discharge of immunologically bound F anti-R IgG. The alternative explanation of regurgitation triggered off by immune complexes is considered less likely in view of the lack of HRP unloading.

https://rupress.org/jcb/article-pdf/82/2/466/1073846/466.pdf

André Trouet

Papers

A covalent linkage between daunorubicin and proteins that is stable in serum and reversible by lysosomal hydrolases, as required for a lysosomotropic drug-carrier conjugate: in vitro and in vivo studies.

Chemotherapy through lysosomes with a DNA-daunorubicin complex.

Nanocapsules: A new type of lysosomotropic carrier

The uptake and intracellular accumulation of aminoglycoside antibiotics in lysosomes of cultured rat fibroblasts.

Fate of plasma membrane during endocytosis. II. Evidence for recycling (shuttle) of plasma membrane constituents