Pharmaceutical Applications and Safety Review of Dendrimers

This article describes the innovative approaches to overcome the cationic toxicity inherently associated with the dendrimers. A dendrimer is a macromolecule characterized by its highly branched 3D structure that provides a high degree of surface functionality and versatility. The toxicity is attributed to the interaction of surface cationic charge of dendrimers with negatively charged biological membranes in vivo. Dendrimer toxicity in biological system is generally characterized by hemolytic toxicity, cytotoxicity and hematological toxicity. To minimize this toxicity, two strategies have been utilized; first, designing and synthesis of biocompatible dendrimers; and second, masking of peripheral charge of dendrimers by surface engineering. Biocompatible dendrimers can be synthesized by employing biodegradable core and branching units or utilizing intermediates of various metabolic pathways. Dendrimer biocompatibility has been evaluated in vitro and in vivo for efficient presentation of biological performance. Neutral and negatively charged dendrimers do not interact with biological environment and hence are compatible for clinical applications as elucidated by various studies examined in this review. Chemical modification of the surface is an important strategy to overcome the toxicity problems associated with the dendrimers.

Download Full-text

Antioxidant Activity, Phenolic Content and Hematoprotective Effects of Cleome arabica Polyphenolic Leaf Extract

Phytothérapie ◽

10.3166/phyto-2019-0206 ◽

2019 ◽

Author(s):

C. Tigrine ◽

A. Kameli

Keyword(s):

Antioxidant Activity ◽

Biological Effects ◽

Reducing Power ◽

Hematological Toxicity ◽

Protective Effects ◽

Ferrous Ions ◽

Polyphenolic Extract ◽

Cleome Arabica

In this study a polyphenolic extract from Cleome arabica leaves (CALE) was investigated for its antioxidant activity in vitro using DPPH•, metal chelating and reducing power methods and for its protective effects against AraC-induced hematological toxicity in vivo using Balb C mice. Results indicated that CALE exhibited a strong and dose-dependent scavenging activity against the DPPH• free radical (IC50 = 4.88 μg/ml) and a high reducing power activity (EC50 = 4.85 μg/ml). Furthermore, it showed a good chelating effects against ferrous ions (IC50 = 377.75 μg/ml). The analysis of blood showed that subcutaneous injection of AraC (50 mg/kg) to mice during three consecutive days caused a significant myelosupression (P < 0.05). The combination of CALE and AraC protected blood cells from a veritable toxicity. Where, the number of the red cells, the amount of hemoglobin and the percentage of the hematocrite were significantly high. On the other hand, AraC cause an elevation of body temperature (39 °C) in mice. However, the temperature of the group treated with CALE and AraC remained normal and did not exceed 37.5 °C. The observed biological effects of CALE, in vitro as well as in vivo, could be due to the high polyphenol and flavonoid contents. In addition, the antioxidant activity of CALE suggested to be responsible for its hematoprotective effect.

Download Full-text

Synthesis, Characterization and in vivo Evaluation of PEGylated PPI Dendrimer for Safe and Prolonged Delivery of Insulin

Drug Delivery Letters ◽

10.2174/2210303109666190401231920 ◽

2019 ◽

Vol 9 (3) ◽

pp. 248-263 ◽

Cited By ~ 1

Author(s):

Ashish K. Parashar ◽

Preeti Patel ◽

Arun K. Gupta ◽

Neetesh K. Jain ◽

Balak Das Kurmi

Keyword(s):

Blood Glucose ◽

Drug Release ◽

Blood Glucose Level ◽

Glucose Level ◽

Albino Rats ◽

Sustained Delivery ◽

In Vivo Evaluation ◽

Hemolytic Toxicity

Background: The present study was aimed at developing and exploring the use of PEGylated Poly (propyleneimine) dendrimers for the delivery of an anti-diabetic drug, insulin. Methods: For this study, 4.0G PPI dendrimer was synthesized by successive Michael addition and exhaustive amidation reactions, using ethylenediamine as the core and acrylonitrile as the propagating agent. Two different activated PEG moieties were employed for PEGylation of PPI dendrimers. Various physicochemical and physiological parameters UV, IR, NMR, TEM, DSC, drug entrapment, drug release, hemolytic toxicity and blood glucose level studies of both PEGylated and non- PEGylated dendritic systems were determined and compared. Results: PEGylation of PPI dendrimers caused increased solubilization of insulin in the dendritic framework as well as in PEG layers, reduced drug release and hemolytic toxicity as well as increased therapeutic efficacy with reduced side effects of insulin. These systems were found to be suitable for sustained delivery of insulin by in vitro and blood glucose-level studies in albino rats, without producing any significant hematological disturbances. Conclusion: Thus, surface modification of PPI dendrimers with PEG molecules has been found to be a suitable approach to utilize it as a safe and effective nano-carrier for drug delivery.

Download Full-text

On the origin of the increased tissue iron content in graded magnesium deficiency states in the rat

British Journal Of Nutrition ◽

10.1079/bjn19970046 ◽

1997 ◽

Vol 77 (3) ◽

pp. 475-490 ◽

Cited By ~ 3

Author(s):

Klaus Schumann ◽

Annette Lebeau ◽

Ursula Gresser ◽

Theodor Gunther ◽

Jürgen Vormann

Keyword(s):

Haemolytic Anaemia ◽

Rapid Growth ◽

Magnesium Deficiency ◽

Erythropoietic Activity ◽

Mg Deficiency ◽

Adequate Diet ◽

Fe Content ◽

High Degree

To investigate the mechanism of tissue Fe accumulation in graded Mg deficiency rats were fed on diets of different Mg contents (70, 110, 208, 330, and 850 mg Mg/kg) for 10, 20, and 30 d during rapid growth. There was no significant impact of Mg deficiency or high luminal Mg concentrations on intestinal59Fe transferin vitroorin vivo. Plasma Mg concentrations and body weight started to decrease after 10 d. Significant haemolytic anaemia was observed after 20 d with siderosis in liver and spleen developing in parallel. Anaemia showed no features of Fe deficiency or infiammation. Comparison between the 70 mg Mg/kg group and animals that received the same quantity of a Mg-adequate diet (850 mg Mg/kg) permitted estimation of quantities of Fe liberated by haemolysis and the increased Fe content in liver and spleen. Both variables showed a high degree of correlation, indicating that the excess of liberated haemoglobin Fe was stored in the tissue. The erythropoietic activity was high during rapid growth, i.e. at days 10 and 20 and decreased significantly after 30 d in all except the most Mg-deficient groups. However, haemolytic anaemia developed because even the high erythropoietic activity in the 70 and 110 mg Mg/kg groups was not sutlicient to recycle all haemoglobin Fe liberated by haemolysis. After 30 d of Mg-deficient feeding the erythrocyte Mg content had decreased to 40% of control values. According to the literature Mg-deficient erythrocytes have a decreased survival time which is likely to be the cause of the observed haemolysis.

Download Full-text

Developmental regulation of heterochromatin-mediated gene silencing in Drosophila

Development ◽

10.1242/dev.125.12.2223 ◽

1998 ◽

Vol 125 (12) ◽

pp. 2223-2234 ◽

Cited By ~ 1

Author(s):

B.Y. Lu ◽

J. Ma ◽

J.C. Eissenberg

Keyword(s):

Cell Cycle ◽

Gene Silencing ◽

Mitotic Activity ◽

Larval Stage ◽

Developmental Regulation ◽

Promoter Strength ◽

Lacz Gene ◽

High Degree

The roles of differentiation, mitotic activity and intrinsic promoter strength in the maintenance of heterochromatic silencing were investigated during development using an inducible lacZ gene as an in vivo probe. Heterochromatic silencing is initiated at the onset of gastrulation, approximately 1 hour after heterochromatin is first visible cytologically. A high degree of silencing is maintained in the mitotically active imaginal cells from mid-embryogenesis until early third instar larval stage, and extensive relaxation of silencing is tightly associated with the onset of differentiation. Relaxation of silencing can be triggered in vitro by ecdysone. In contrast, timing and extent of silencing at both the initiation and relaxation stages are insensitive to changes in cell cycle activity, and intrinsic promoter strength also does not influence the extent of silencing by heterochromatin. These data suggest that the silencing activity of heterochromatin is developmentally programmed.

Download Full-text

Toxicity And Surface Modification Of Dendrimers: A Critical Review

Current Drug Delivery ◽

10.2174/1567201818666211021160441 ◽

2021 ◽

Vol 18 ◽

Author(s):

Rohini Kharwade ◽

Payal Badole ◽

Nilesh Mahajan ◽

Sachin More

Keyword(s):

Surface Modification ◽

Positive Charge ◽

Haematological Toxicity ◽

Three Dimensional ◽

Different Types ◽

Hemolytic Toxicity ◽

High Degree ◽

Core Functionality ◽

Polymeric Structures

: As compared to other nano polymers, dendrimers have novel three dimensional, synthetic hyperbranched, nano-polymeric structures. The characteristic of these supramolecular dendritic structures has a high degree of significant surface as well as core functionality in the transportation of drugs for targeted therapy, specifically in host-guest response, gene transfer therapy and imaging of biological systems. However, there are conflicting shreds of evidence regarding biological safety and dendrimers toxicity due to their positive charge at the surface. It includes cytotoxicity, hemolytic toxicity, haematological toxicity, immunogenicity and in vivo toxicity. Therefore to resolve these problems surface modification of the dendrimer group is one of the methods. From that point, this review involves different strategies which reduce the toxicity and improve the biocompatibility of different types of dendrimers. From that viewpoint, we broaden the structural and safe characteristics of the dendrimers in the biomedical and pharmaceutical fields.

Download Full-text

Isolation and characterization of adrenocortical progenitors involved in the adaptation to stress

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1814072115 ◽

2018 ◽

Vol 115 (51) ◽

pp. 12997-13002 ◽

Cited By ~ 15

Author(s):

Charlotte Steenblock ◽

Maria F. Rubin de Celis ◽

Luis F. Delgadillo Silva ◽

Verena Pawolski ◽

Ana Brennand ◽

...

Keyword(s):

Lineage Tracing ◽

Differentiated Cells ◽

Isolation And Characterization ◽

Proliferation And Differentiation ◽

Response To Stress ◽

Steroidogenic Cells ◽

High Degree

The adrenal gland is a master regulator of the human body during response to stress. This organ shows constant replacement of senescent cells by newly differentiated cells. A high degree of plasticity is critical to sustain homeostasis under different physiological demands. This is achieved in part through proliferation and differentiation of adult adrenal progenitors. Here, we report the isolation and characterization of a Nestin+ population of adrenocortical progenitors located under the adrenal capsule and scattered throughout the cortex. These cells are interconnected with progenitors in the medulla. In vivo lineage tracing revealed that, under basal conditions, this population is noncommitted and slowly migrates centripetally. Under stress, this migration is greatly enhanced, and the cells differentiate into steroidogenic cells. Nestin+ cells cultured in vitro also show multipotency, as they differentiate into mineralocorticoid and glucocorticoid-producing cells, which can be further influenced by the exposure to Angiotensin II, adrenocorticotropic hormone, and the agonist of luteinizing hormone-releasing hormone, triptorelin. Taken together, Nestin+ cells in the adult adrenal cortex exhibit the features of adrenocortical progenitor cells. Our study provides evidence for a role of Nestin+ cells in organ homeostasis and emphasizes their role under stress. This cell population might be a potential source of cell replacement for the treatment of adrenal insufficiency.

Download Full-text

Transcriptomic-Based Quantification of the Epithelial-Hybrid-Mesenchymal Spectrum Across Biological Contexts

Biomolecules ◽

10.3390/biom12010029 ◽

2021 ◽

Vol 12 (1) ◽

pp. 29

Author(s):

Susmita Mandal ◽

Tanishq Tejaswi ◽

Rohini Janivara ◽

Syamanthak Srikrishnan ◽

Pradipti Thakur ◽

...

Keyword(s):

Cancer Cells ◽

Cancer Metastasis ◽

Expression Profiles ◽

Gene List ◽

Cellular Reprogramming ◽

Induced Pluripotent ◽

Patient Prognosis ◽

High Degree

Epithelial-mesenchymal plasticity (EMP) underlies embryonic development, wound healing, and cancer metastasis and fibrosis. Cancer cells exhibiting EMP often have more aggressive behavior, characterized by drug resistance, and tumor-initiating and immuno-evasive traits. Thus, the EMP status of cancer cells can be a critical indicator of patient prognosis. Here, we compare three distinct transcriptomic-based metrics—each derived using a different gene list and algorithm—that quantify the EMP spectrum. Our results for over 80 cancer-related RNA-seq datasets reveal a high degree of concordance among these metrics in quantifying the extent of EMP. Moreover, each metric, despite being trained on cancer expression profiles, recapitulates the expected changes in EMP scores for non-cancer contexts such as lung fibrosis and cellular reprogramming into induced pluripotent stem cells. Thus, we offer a scoring platform to quantify the extent of EMP in vitro and in vivo for diverse biological applications including cancer.

Download Full-text

Proteomic and 3D structure analyses highlight the C/D box snoRNP assembly mechanism and its control

The Journal of Cell Biology ◽

10.1083/jcb.201404160 ◽

2014 ◽

Vol 207 (4) ◽

pp. 463-480 ◽

Cited By ~ 35

Author(s):

Jonathan Bizarro ◽

Christophe Charron ◽

Séverine Boulon ◽

Belinda Westman ◽

Bérengère Pradet-Balade ◽

...

Keyword(s):

Isotope Labeling ◽

Core Protein ◽

3D Structure ◽

Assembly Mechanism ◽

Core Proteins ◽

Assembly Factors ◽

Assembly Factor

In vitro, assembly of box C/D small nucleolar ribonucleoproteins (snoRNPs) involves the sequential recruitment of core proteins to snoRNAs. In vivo, however, assembly factors are required (NUFIP, BCD1, and the HSP90–R2TP complex), and it is unknown whether a similar sequential scheme applies. In this paper, we describe systematic quantitative stable isotope labeling by amino acids in cell culture proteomic experiments and the crystal structure of the core protein Snu13p/15.5K bound to a fragment of the assembly factor Rsa1p/NUFIP. This revealed several unexpected features: (a) the existence of a protein-only pre-snoRNP complex containing five assembly factors and two core proteins, 15.5K and Nop58; (b) the characterization of ZNHIT3, which is present in the protein-only complex but gets released upon binding to C/D snoRNAs; (c) the dynamics of the R2TP complex, which appears to load/unload RuvBL AAA+ adenosine triphosphatase from pre-snoRNPs; and (d) a potential mechanism for preventing premature activation of snoRNP catalytic activity. These data provide a framework for understanding the assembly of box C/D snoRNPs.

Download Full-text

Cationic Substitutions in Hydroxyapatite: Current Status of the Derived Biofunctional Effects and Their In Vitro Interrogation Methods

Materials ◽

10.3390/ma11112081 ◽

2018 ◽

Vol 11 (11) ◽

pp. 2081 ◽

Cited By ~ 55

Author(s):

Teddy Tite ◽

Adrian-Claudiu Popa ◽

Liliana Balescu ◽

Iuliana Bogdan ◽

Iuliana Pasuk ◽

...

Keyword(s):

High Performance ◽

Life Time ◽

Crystalline Lattice ◽

Current Status ◽

Synthesis Methods ◽

Biological Interactions ◽

Application Range ◽

Biological Performance

High-performance bioceramics are required for preventing failure and prolonging the life-time of bone grafting scaffolds and osseous implants. The proper identification and development of materials with extended functionalities addressing socio-economic needs and health problems constitute important and critical steps at the heart of clinical research. Recent findings in the realm of ion-substituted hydroxyapatite (HA) could pave the road towards significant developments in biomedicine, with an emphasis on a new generation of orthopaedic and dentistry applications, since such bioceramics are able to mimic the structural, compositional and mechanical properties of the bone mineral phase. In fact, the fascinating ability of the HA crystalline lattice to allow for the substitution of calcium ions with a plethora of cationic species has been widely explored in the recent period, with consequent modifications of its physical and chemical features, as well as its functional mechanical and in vitro and in vivo biological performance. A comprehensive inventory of the progresses achieved so far is both opportune and of paramount importance, in order to not only gather and summarize information, but to also allow fellow researchers to compare with ease and filter the best solutions for the cation substitution of HA-based materials and enable the development of multi-functional biomedical designs. The review surveys preparation and synthesis methods, pinpoints all the explored cation dopants, and discloses the full application range of substituted HA. Special attention is dedicated to the antimicrobial efficiency spectrum and cytotoxic trade-off concentration values for various cell lines, highlighting new prophylactic routes for the prevention of implant failure. Importantly, the current in vitro biological tests (widely employed to unveil the biological performance of HA-based materials), and their ability to mimic the in vivo biological interactions, are also critically assessed. Future perspectives are discussed, and a series of recommendations are underlined.

Download Full-text

Increased Carrier Peptide Stability through pH Adjustment Improves Insulin and PTH(1-34) Delivery In Vitro and In Vivo Rather than by Enforced Carrier Peptide-Cargo Complexation

Pharmaceutics ◽

10.3390/pharmaceutics12100993 ◽

2020 ◽

Vol 12 (10) ◽

pp. 993

Author(s):

Mie Kristensen ◽

Ragna Guldsmed Diedrichsen ◽

Valeria Vetri ◽

Vito Foderà ◽

Hanne Mørck Nielsen

Keyword(s):

Oral Delivery ◽

Molecular Size ◽

Therapeutic Peptide ◽

Enzymatic Stability ◽

Therapeutic Peptides ◽

Ph Dependent ◽

Pharmacologically Active ◽

High Degree

Oral delivery of therapeutic peptides is hampered by their large molecular size and labile nature, thus limiting their permeation across the intestinal epithelium. Promising approaches to overcome the latter include co-administration with carrier peptides. In this study, the cell-penetrating peptide penetratin was employed to investigate effects of co-administration with insulin and the pharmacologically active part of parathyroid hormone (PTH(1-34)) at pH 5, 6.5, and 7.4 with respect to complexation, enzymatic stability, and transepithelial permeation of the therapeutic peptide in vitro and in vivo. Complex formation between insulin or PTH(1-34) and penetratin was pH-dependent. Micron-sized complexes dominated in the samples prepared at pH-values at which penetratin interacts electrostatically with the therapeutic peptide. The association efficiency was more pronounced between insulin and penetratin than between PTH(1-34) and penetratin. Despite the high degree of complexation, penetratin retained its membrane activity when applied to liposomal structures. The enzymatic stability of penetratin during incubation on polarized Caco-2 cell monolayers was pH-dependent with a prolonged half-live determined at pH 5 when compared to pH 6.5 and 7.4. Also, the penetratin-mediated transepithelial permeation of insulin and PTH(1-34) was increased in vitro and in vivo upon lowering the sample pH from 7.4 or 6.5 to 5. Thus, the formation of penetratin-cargo complexes with several molecular entities is not prerequisite for penetratin-mediated transepithelial permeation a therapeutic peptide. Rather, a sample pH, which improves the penetratin stability, appears to optimize the penetratin-mediated transepithelial permeation of insulin and PTH(1-34).

Download Full-text