Improved Tissue Selectivity Research Articles

PVA-Stabilized and Coassembled Nano/Microparticles with High Payload of Dual Phytochemicals for Enhanced Antibacterial and Targeting Effect.

The codelivery of multiple bioactive phytochemicals via nano/microparticles (NPs/MPs) represents a promising strategy for enhancing therapeutic efficacy. This study presents the development of novel poly(vinyl alcohol) (PVA)-stabilized hybrid particles designed for codelivery of palmatine hydrochloride (PAL) and glycyrrhizic acid (GL). Employing a straightforward coassembly method, we synthesized dual-drug particles achieving a high payload capacity of over 70%. The particles were characterized as uniform in size, within the nano/micron range, and exhibited a ζ-potential of -5.0 mV. The incorporation of PVA not only stabilized the particles but also refined the aggregation process, resulting in more uniform and finer particles approximately 1 μm in size. Spectral analysis and molecular dynamics simulations verified the presence of π-π stacking and hydrogen bonding between PAL and GL within the particles. In vitro antibacterial assays indicated that the hybrid particles had a lower minimum inhibitory concentration against Escherichia coli and Multidrug-Resistant Staphylococcus aureus than those of the pure drugs. In vivo biodistribution study in rats revealed that the PVA-stabilized particles revealed enhanced targeting to the liver, lung, and heart, demonstrating improved tissue selectivity compared with the solution group. In summary, the PVA-stabilized hybrid NPs/MPs represent an innovative and efficient platform for codelivery of multidrugs. These findings highlight the promise of coassembled particles for high loading, enhanced bioactivity, and targeted delivery, making them a strong candidate for future clinical applications.

Systemic Effects of Photoactivated 5,10,15,20-tetrakis(N-methylpyridinium-3-yl) Porphyrin on Healthy Drosophila melanogaster.

Porphyrins are frequently employed in photodynamic therapy (PDT), a non-invasive technique primarily utilized to treat subcutaneous cancers, as photosensitizing agents (PAs). The development of a new PA with improved tissue selectivity and efficacy is crucial for expanding the application of PDT for the management of diverse cancers. We investigated the systemic effects of 5,10,15,20-tetrakis(N-methylpyridinium-3-yl)-porphyrin (TMPyP3) using Drosophila melanogaster adult males. We established the oral administration schedule and demonstrated that TMPyP3 was absorbed and stored higher in neuronal than in non-neuronal extracts. Twenty-four hours after oral TMPyP3 photoactivation, the quantity of hydrogen peroxide (H2O2) increased, but exclusively in the head extracts. Regardless of photoactivation, TMPyP3 resulted in a reduced concentration of H2O2 after 7 days, and this was linked with a decreased capacity to climb, as indicated by negative geotaxis. The findings imply that systemic TMPyP3 therapy may disrupt redox regulation, impairing cellular signaling and behavioral outcomes in the process. To determine the disruptive effect of porphyrins on redox homeostasis, its duration, and the mechanistic variations in retention across various tissues, more research is required.

Advantage of ostarine over raloxifene and their combined treatments for muscle of estrogen-deficient rats

PurposeSelective androgen (ostarine, OST) and estrogen (raloxifene, RAL) receptor modulators with improved tissue selectivity have been developed as alternatives to hormone replacement therapy. We investigated the combined effects of OST and RAL on muscle tissue in an estrogen-deficient rat model of postmenopausal conditions.MethodsThree-month-old Sprague Dawley rats were divided into groups: (1) untreated non-ovariectomized rats (Non-OVX), (2) untreated ovariectomized rats (OVX), (3) OVX rats treated with OST, (4) OVX rats treated with RAL, (5) OVX rats treated with OST and RAL. Both compounds were administered in the diet. The average dose received was 0.6 ± 0.1 mg for OST and 11.1 ± 1.2 mg for RAL per kg body weight/day. After thirteen weeks, rat activity, muscle weight, structure, gene expression, and serum markers were analyzed.ResultsOST increased muscle weight, capillary ratio, insulin-like growth factor 1 (Igf-1) expression, serum phosphorus, uterine weight. RAL decreased muscle weight, capillary ratio, food intake, serum calcium and increased Igf-1 and Myostatin expression, serum follicle stimulating hormone (FSH). OST + RAL increased muscle nucleus ratio, uterine weight, serum phosphorus, FSH and luteinizing hormone and decreased body and muscle weight, serum calcium. Neither treatment changed muscle fiber size. OVX increased body and muscle weight, decreased uterine weight, serum calcium and magnesium.ConclusionOST had beneficial effects on muscle in OVX rats. Side effects of OST on the uterus and serum electrolytes should be considered before using it for therapeutic purposes. RAL and RAL + OST had less effect on muscle and showed endocrinological side effects on pituitary–gonadal axis.

Nanoparticle Formulations of Poly (ADP-ribose) Polymerase Inhibitors for Cancer Therapy.

A number of poly(ADP-ribose) polymerase (PARP) inhibitors have been recently approved for clinical use in BRCA mutated and other cancers. However, off-target toxicity of PARP inhibitors and the emergence of drug resistance following prolonged administration of these inhibitors indicate the need for improved methods of drug delivery to the tumors. Nanomedicines based upon nanoparticle formulations of conventional small molecule drugs and inhibitors offer many advantages, such as increased solubility and bioavailability of drugs, reduced toxicity and drug resistance, and improved tissue selectivity and therapeutic efficacy. This review highlights the current trends in formulations of PARP inhibitors developed by nanotechnology approaches and provides an insight into the applications and limitations of these PARP inhibitor nanomedicines for cancer therapies.

Combinatorial expression of GPCR isoforms affects signalling and drug responses.

G-protein-coupled receptors (GPCRs) are membrane proteins that modulate physiology across human tissues in response to extracellular signals. GPCR-mediated signalling can differ because of changes in the sequence1,2 or expression3 of the receptors, leading to signalling bias when comparing diverse physiological systems4. An underexplored source of such bias is the generation of functionally diverse GPCR isoforms with different patterns of expression across different tissues. Here we integrate data from human tissue-level transcriptomes, GPCR sequences and structures, proteomics, single-cell transcriptomics, population-wide genetic association studies and pharmacological experiments. We show how a single GPCR gene can diversify into several isoforms with distinct signalling properties, and how unique isoform combinations expressed in different tissues can generate distinct signalling states. Depending on their structural changes and expression patterns, some of the detected isoforms may influence cellular responses to drugs and represent new targets for developing drugs with improved tissue selectivity. Our findings highlight the need to move from a canonical to a context-specific view of GPCR signalling that considers how combinatorial expression of isoforms in a particular cell type, tissue or organism collectively influences receptor signalling and drug responses.

A Series of 2,4-Disubstituted Quinolines as a New Class of Allosteric Enhancers of the Adenosine A3 Receptor

The adenosine receptor subfamily consists of the adenosine A(1), A(2A), A(2B), and A(3) receptors, which are localized in a variety of tissues throughout the human body. It is, therefore, a challenge to develop receptor specific ligands with improved tissue selectivity. Allosteric modulators could have these therapeutic advantages over orthosteric ligands. In the present study, a series of 2,4-disubstituted quinolines were synthesized on the basis of the structure of LUF6000 (34). Compound 27 (LUF6096) was able to allosterically enhance agonist binding to a similar extent as 34. In addition, this new compound showed low, if any, orthosteric affinity for any of the adenosine receptors. In a functional assay, compound 27 showed improved activity in comparison to 34, as it increased both the intrinsic efficacy and the potency of the reference agonist Cl-IB-MECA at the human adenosine A(3) receptor.

A Dual-Targeted Lentiviral Vector Homing in on Prostate Bone Metastases

A Dual-Targeted Lentiviral Vector Homing in on Prostate Bone Metastases

Activities of estrogen receptor alpha- and beta-selective ligands at diverse estrogen responsive gene sites mediating transactivation or transrepression

Estrogens exert their regulatory transcriptional effects, which can be stimulatory or repressive, at diverse gene sites via two estrogen receptors, ERα and ERβ. Since these two ERs have different tissue distributions, ligands that have the capacity to selectively activate or inhibit these two ERs would be useful in elucidating the biology of these two receptors and might assist in the development of estrogen pharmaceuticals with improved tissue selectivity. We have developed several ligands that showed ERα or ERβ selectivity at promoter-gene sites containing consensus estrogen response elements (EREs): ERα-selective agonist (propyl-pyrazole-triol (PPT)), ERα-selective antagonist (methyl-piperidino-pyrazole (MPP)), ERβ-potency selective agonist (diarylpropionitrile (DPN)) and ERβ-selective antagonist/ERα-agonist (R,R-tetrahydrochrysene (R,R-THC)). In this study, we have examined the activity of these compounds at a range of gene sites where ER stimulates gene expression through non-consensus EREs (complement C3), or multiple half-EREs (NHE-RF/EBP50), or by tethering to DNA via other proteins (TGF β3 and progesterone receptor A/AP-1), and at gene sites where ER represses gene transcription (interleukin-6). At all of these genes, PPT showed full stimulation through ERα while displaying no agonism through ERβ. MPP antagonized estradiol actions on gene transactivation and transrepression through ERα, with little or no effect on transcription mediated through ERβ. DPN displayed subtype-selective agonism, being ca. 30-fold more potent through ERβ. R,R-THC was a complete antagonist through ERβ and displayed agonism through ERα, the level of which was promoter dependent. Because these ligands maintain their agonist or antagonist character and ER subtype-selectivity at gene sites of diverse nature, where estradiol is either stimulatory or inhibitory, these compounds should prove useful in elucidating the biological functions of ERα and ERβ.

De novo design, synthesis, and evaluation of novel nonsteroidal phenanthrene ligands for the estrogen receptor.

Although there are many estrogen receptor antagonists with improved tissue selectivity profiles compared with tamoxifen, optimal tissue selectivity has not yet been demonstrated. As such there is still a need for additional diversity and new chemical scaffolds to allow for exploration of improved tissue selectivity. Here, we describe the discovery of a novel phenanthrene scaffold for estrogen receptor ligands utilizing a ligand based de novo design approach. The nanomolar binding of phenanthrenes, 12b,c, 14b,c, and 15 against human recombinant ER(alpha) indicates that our ligand based de novo design approach was successful. From a gene transfection assay, 12b,c, 14b,c, and 15 displayed only antagonistic activity with no observable agonistic activity. The alkyl 9,10-dihydrophenanthrene 16 (presumably a racemic mixture) was a substantially more potent ER binder than the phenanthrenes. It also displayed only antagonistic activity and was effective at inhibiting estradiol stimulated MCF-7 cell proliferation. These results demonstrate that this phenanthrene (and 9,10-dihydrophenanthrene) scaffold warrants further study as potential selective estrogen receptor modulators and/or pure antiestrogens.

De novo design, synthesis and evaluation of a non-steroidal diphenylnaphthyl propylene ligand for the estrogen receptor

There is still a strong need for additional diversity and new chemical scaffolds to allow for the exploration of improved tissue selectivity and finding better selective estrogen receptor modulators (SERMs). Using a de novo design technology a diphenylnaphthyl propylene scaffold, exemplified by (E)-9b, with ER antagonist activity has been generated. It was prepared by alkylating 1-[4-methoxyphenyl)-2-(4-(2-chloroethoxy)phenyl]-1-propanone under metal halogen exchange conditions with 1-iodo-6-methoxy-naphthalene. Following dehydration and cleavage of the methoxy groups, (E)-9b was formed by displacement of the chloro group with pyrrolidine. (E)-9b binding to ER generated calculated Ki values of 3.7 nM for hERα and 72 nM for hERβ. The antagonism of (E)-9b was demonstrated in cell transfection assays using the ERE from the vitA2 promotor and the natural ER-responsive pS2 promotor. With increasing concentrations of (E)-9b, the E2-dependent response was efficiently inhibited demonstrating that (E)-9b could function as an anti-estrogen in these assays. Interestingly, ERα activity was inhibited even below basal levels suggesting that ligand-independent activity of ERα was also inhibited. Computational docking studies suggest that the placement of the hydroxyl group on the naphthalene group may not be optimal and we are currently exploring additional analogues.

Conformational Changes and Coactivator Recruitment by Novel Ligands for Estrogen Receptor- and Estrogen Receptor- : Correlations with Biological Character and Distinct Differences among SRC Coactivator Family Members

Ligands for the estrogen receptor (ER) that have the capacity to selectively bind to or activate the ER subtypes ERα or ERβ would be useful in elucidating the biology of these two receptors and might assist in the development of estrogen pharmaceuticals with improved tissue selectivity. In this study, we examine three compounds of novel structure that act as ER subtype-selective ligands. These are a propyl pyrazole triol (PPT), which is a potent agonist on ERα but is inactive on ERβ, and a pair of substituted tetrahydrochrysenes (THC), one enantiomer of which (S,S-THC) is an agonist on both ERα and ERβ, the other (R,R-THC) being an agonist on ERα but an antagonist on ERβ. To investigate the molecular mechanisms underlying the ER subtype-selective actions of these compounds, we have determined the conformational changes induced in ERα and ERβ by these ligands using protease digestion sensitivity, and we have tested the ability of these ligands to promote the recruitment of representatives of the three SRC/p160 coactivator protein family members (SRC-1, GRIP-1, ACTR, respectively) to ERα and ERβ using yeast two-hybrid and glutathione-S-transferase (GST) pull-down assays. We find that the ligand-ER protease digestion pattern is distinctly different for stimulatory and inhibitory ligands, and that this assay, as well as coactivator recruitment, are excellent indicators of their agonist/antagonist character. Interestingly however, compared with estradiol, the novel agonist ligands show some quantitative differences in their ability to recruit SRC-1, -2, and -3. This implies that while generally similar to estradiol, these ligands induce ER conformations that differ somewhat from that induced by estradiol, differences that are illustrative of the nature of their biological character. The application of methods to characterize the conformations induced in ER subtypes by novel ligands, as done in this study, enables a greater understanding of how ligand-receptor conformations relate to estrogen agonist or antagonist behavior.

Conformational changes and coactivator recruitment by novel ligands for estrogen receptor-alpha and estrogen receptor-beta: correlations with biological character and distinct differences among SRC coactivator family members.

Ligands for the estrogen receptor (ER) that have the capacity to selectively bind to or activate the ER subtypes ERalpha or ERbeta would be useful in elucidating the biology of these two receptors and might assist in the development of estrogen pharmaceuticals with improved tissue selectivity. In this study, we examine three compounds of novel structure that act as ER subtype-selective ligands. These are a propyl pyrazole triol (PPT), which is a potent agonist on ERalpha but is inactive on ERbeta, and a pair of substituted tetrahydrochrysenes (THC), one enantiomer of which (S,S-THC) is an agonist on both ERalpha and ERbeta, the other (R,R-THC) being an agonist on ERalpha but an antagonist on ERbeta. To investigate the molecular mechanisms underlying the ER subtype-selective actions of these compounds, we have determined the conformational changes induced in ERalpha and ERbeta by these ligands using protease digestion sensitivity, and we have tested the ability of these ligands to promote the recruitment of representatives of the three SRC/p160 coactivator protein family members (SRC-1, GRIP-1, ACTR, respectively) to ERalpha and ERbeta using yeast two-hybrid and glutathione-S-transferase (GST) pull-down assays. We find that the ligand-ER protease digestion pattern is distinctly different for stimulatory and inhibitory ligands, and that this assay, as well as coactivator recruitment, are excellent indicators of their agonist/antagonist character. Interestingly however, compared with estradiol, the novel agonist ligands show some quantitative differences in their ability to recruit SRC-1, -2, and -3. This implies that while generally similar to estradiol, these ligands induce ER conformations that differ somewhat from that induced by estradiol, differences that are illustrative of the nature of their biological character. The application of methods to characterize the conformations induced in ER subtypes by novel ligands, as done in this study, enables a greater understanding of how ligand-receptor conformations relate to estrogen agonist or antagonist behavior.

Potassium channel openers: pharmacological and clinical aspects.

Opening of plasmalemmal K+ channels leads to cellular hyperpolarization which, in excitable tissues possessing voltage-dependent Ca2+ channels, prevents the opening of such channels and thus prevents excitation. In the last few years, an increasing number of compounds have been identified which elicit their effects by opening K+ channels, preferentially in smooth muscle, but also in other excitable tissues. These include the novel benzpyrans, cromakalim and bimakalim, the thioformamide aprikalim, and also well known antihypertensives such as minoxidil sulphate, diazoxide and pinacidil. After a short overview of the various families of K+ channel openers (KCOs), their basic pharmacological properties, including inhibition by the sulfonyl ureas (such as glibenclamide) are presented. The actual discussion concerning the type of K+ channel(s) opened by these compounds and their mechanism(s) of vasorelaxation will be reported. The therapeutic potential of these compounds in the cardiovascular field (as antihypertensives and, in particular, as anti-ischemic agents in heart and skeletal muscle), and in asthma (where they reverse established airway hyperreactivity) will also be discussed. Improved tissue selectivity may be the essential pre-requisite for true clinical success of this class of compounds.

Structure activity studies leading to a tissue-selective hypotensive prostaglandin analog, 13,14-dihydro-16-phenyl-ω-tetranor PGE 2

During our systematic search for prostaglandins with improved tissue selectivity and metabolic stability, we synthesized a series of PGE 2 analogs in which the n-amyl carbinol side chain was systematically substituted by a phenyl ring, based on structural considerations incorporating the 17,18- cis-double bond of PGE 3 into an aromatic ring. These compounds were evaluated for uterine stimulant, bronchodilator and hypotensive activity. Among the divergent biological profiles exhibited by these analogs, noteworthy was the tissue-selective hypotensive profile displayed by 13,14-dihydro-16-phenyl-ω-tetranor PGE 2.