Search Results (29)

Background: D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), an amphiphilic derivative of natural vitamin E, functions as both a drug efflux inhibitor and a protector against enzymatic degradation and has been widely incorporated into nano-formulations for drug design and delivery. Objective: This systematic review evaluates TPGS-based organic nanocarriers, emphasizing their potential to enhance bioavailability of active compounds which include drugs and phytochemicals, improve pharmacokinetic profiles, and optimize therapeutic outcomes, eventually overcoming the limitations of conventional oral active compounds delivery. Search strategy: Data collection was carried out by entering key terms (TPGS) AND (Micelle OR Liposome OR Nanoparticle OR Nanotube OR Dendrimer OR Niosome OR Nanosuspension OR Nanomicelle OR Nanocrystal OR Nanosphere OR Nanocapsule) AND (Oral Bioavailability) into the Scopus database. Inclusion criteria: Full-text articles published in English and relevant to TPGS, which featured organic materials, utilized an oral administration route, and included pharmacokinetic study, were included to the final review. Data extraction and analysis: Data selection was conducted by two review authors and subsequently approved by all other authors through a consensus process. The outcomes of the included studies were reviewed and categorized based on the types of nanocarriers. Results: An initial search of the database yielded 173 records. After screening by title and abstract, 52 full-text articles were analyzed. A total of 21 papers were excluded while 31 papers were used in this review. Conclusions: This review concludes that TPGS-based organic nanocarriers are able to enhance the bioavailability of various active compounds, including several phytochemicals, leveraging TPGS’s amphiphilic nature, inhibition of efflux transporters, protection against degradation, and stabilization properties. Despite using the same excipient, variability in particle size, zeta potential, and encapsulation efficiency among nanocarriers indicates the need for tailored formulations. A comprehensive approach involving the development and standardized comparison of diverse TPGS-incorporated active compound formulations is essential to identify the optimal TPGS-based nanocarrier for improving a particular active compound’s bioavailability. Full article

This perspective begins with an overview of the major impact that the dendron, dendrimer, and dendritic state (DDDS) discovery has made on traditional polymer science. The entire DDDS technology is underpinned by an unprecedented new polymerization strategy referred to as step-growth, amplification-controlled polymerization (SGACP). This new SGACP paradigm allows for routine polymerization of common monomers and organic materials into precise monodispersed, dendritic macromolecules (i.e., dendrons/dendrimers) with nanoscale sizes and structure-controlled features that match and rival discrete in vivo biopolymers such as proteins and nucleic acids (i.e., DNA, siRNA, mRNA, etc.). These dendritic architectures exhibit unprecedented new intrinsic properties widely recognized to define a new fourth major polymer architecture class, namely: Category (IV): dendrons, dendrimers, and random hyperbranched polymers after traditional categories: (I) linear, (II) cross-linked, and (III) simple-branched types. Historical confusion over the first examples of the structure confirmed and verified cascade, dendron, dendrimer, and arborol syntheses, while associated misuse of accepted dendritic terminology is also reviewed and clarified. The importance of classifying all dendrons and dendrimers based on branch cell symmetry and the significant role of critical nanoscale-design parameters (CNDPs) for optimizing dendritic products for pharma/nanomedicine applications with a focus on enhancing stealth, non-complement activation properties is presented. This is followed by an overview of the extraordinary growth observed for amphiphilic dendron/dendrimer syntheses and their self-assembly into dendritic supramolecular assemblies, as well as many unique applications demonstrated in pharma and nanomedicine, especially involving siRNA delivery and mRNA vaccine development. This perspective is concluded with optimistic expectations predicted for new dendron and dendrimer application roles in pharma, nanomedicine, and life sciences. Full article

Background/Objectives: Current promising treatments for many diseases are based on the use of therapeutic nucleic acids, including DNA. However, the list of nanocarriers is limited due to their low biocompatibility, high cost, and toxicity. The design of synthetic building blocks for creating universal delivery systems for genetic material is an unsolved problem. In this work, we propose PAMAM dendrimers with rigid thiacalixarene core in various conformations, i.e., PAMAM-calix-dendrimers, as a platform for a supramolecular universal constructor for nanomedicine. Results: Third generation PAMAM dendrimers with a macrocyclic core in three conformations (cone, partial cone, and 1,3-alternate) were synthesized for the first time. The obtained dendrimers were capable of binding and compacting calf thymus DNA, whereby the binding efficiency improved with increasing generation, while the influence of the macrocyclic core was reduced. A dramatic effect of the macrocyclic core conformation on the hemolytic activity of PAMAM-calix-dendrimers was observed. Specifically, a notable reduction in hemotoxicity was associated with a decrease in compound amphiphilicity. Conclusions: We hope the results will help reduce financial and labor costs in developing new drug delivery systems based on dendrimers. Full article

Small interfering RNA (siRNA) therapeutics, characterized by high specificity, potency, and durability, hold great promise in the treatment of cancer and other diseases. However, the clinic implementation of siRNA therapeutics critically depends on the safe and on–demand delivery of siRNA to the target cells. Here, we reported a family of ferrocenyl amphiphilic dendrimers (Fc-AmDs) for on–demand delivery of siRNA in response to the high ROS content in cancer cells. These dendrimers bear ROS–sensitive ferrocene moieties in the hydrophobic components and positively chargeable poly(amidoamine) dendrons as the hydrophilic entities, possessing favorable safety profiles and ROS responsive properties. One of these ferrocenyl amphiphilic dendrimers, Fc-C₈-AmD 8A, outperforms in siRNA delivery, benefiting from its optimal balance of hydrophobicity and hydrophilicity. Its ROS feature facilitates specific and efficient disassembly of its complex with siRNA in ROS–rich cancer cells for effective siRNA delivery and gene silencing. Moreover, Fc-C₈-AmD 8A also integrates the features and beneficial properties of both lipid and dendrimer vectors. Therefore, it represents a novel on–demand delivery system for cancer cell–specific siRNA delivery. This work opens new perspectives for designing self–assembly nanosystems for on–demand drug delivery. Full article

Osteoclast stimulatory transmembrane protein (OC-STAMP) plays a pivotal role in the promotion of cell fusion during osteoclast differentiation (osteoclastogenesis) in the context of pathogenic bone resorption. Thus, it is plausible that the suppression of OC-STAMP through a bioengineering approach could lead to the development of an effective treatment for inflammatory bone resorptive diseases with minimum side effects. Here, we synthesized two types of spermine-bearing (Spe) cationic glucan dendrimer (GD) gels (with or without C12) as carriers of short interfering RNA (siRNA) to silence OC-STAMP. The results showed that amphiphilic C12-GD-Spe gel was more efficient in silencing OC-STAMP than GD-Spe gel and that the mixture of anti-OC-STAMP siRNA/C12-GD-Spe significantly downregulated RANKL-induced osteoclastogenesis. Also, local injection of anti-OC-STAMP-siRNA/C12-GD-Spe could attenuate bone resorption induced in a mouse model of periodontitis. These results suggest that OC-STAMP is a promising target for the development of a novel bone regenerative therapy and that C12-GD-Spe gel provides a new nanocarrier platform of gene therapies for osteolytic disease. Full article

Dendrimers, intricate macromolecules with highly branched nanostructures, offer unique attributes including precise control over size, shape, and functionality, making them promising candidates for a wide range of biomedical applications. The exploration of their interaction with biological environments, particularly human serum albumin (HSA), holds significant importance for biomedical utilization. In this study, the interaction between HSA and a recently developed self-assembling amphiphilic dendrimer (AD) was investigated using various experimental techniques. Fluorescence spectroscopy and isothermal titration calorimetry revealed moderate interactions between the protein and the AD nanomicelles (NMs), primarily attributed to favorable enthalpic contributions arising from electrostatic interactions and hydrogen bonding. Structural analysis indicated minimal changes in HSA upon complexation with the AD NMs, which was further supported by computational simulations demonstrating stable interactions at the atomistic level. These findings provide valuable insights into the binding mechanisms and thermodynamic parameters governing HSA/AD NM interactions, thereby contributing to the understanding of their potential biomedical applications. Full article

Viral and synthetic vectors to deliver nucleic acids were key to the rapid development of extraordinarily efficient COVID-19 vaccines. The four-component lipid nanoparticles (LNPs), containing phospholipids, PEG-conjugated lipids, cholesterol, and ionizable lipids, co-assembled with mRNA via a microfluidic technology, are the leading nonviral delivery vector used by BioNTech/Pfizer and Moderna to access COVID-19 mRNA vaccines. LNPs exhibit a statistical distribution of their four components when delivering mRNA. Here, we report a methodology that involves screening libraries to discover the molecular design principles required to realize organ-targeted mRNA delivery and mediate activity with a one-component ionizable multifunctional amphiphilic Janus dendrimer (IAJD) derived from plant phenolic acids. IAJDs co-assemble with mRNA into monodisperse dendrimersome nanoparticles (DNPs) with predictable dimensions, via the simple injection of their ethanol solution in a buffer. The precise location of the functional groups in one-component IAJDs demonstrated that the targeted organs, including the liver, spleen, lymph nodes, and lung, are selected based on the hydrophilic region, while activity is associated with the hydrophobic domain of IAJDs. These principles, and a mechanistic hypothesis to explain activity, simplify the synthesis of IAJDs, the assembly of DNPs, handling, and storage of vaccines, and reduce price, despite employing renewable plant starting materials. Using simple molecular design principles will lead to increased accessibility to a large diversity of mRNA-based vaccines and nanotherapeutics. Full article

In 2022, the Nobel Prize in Chemistry was awarded to Bertozzi, Meldal, and Sharpless “for the development of click chemistry and biorthogonal chemistry”. Since 2001, when the concept of click chemistry was advanced by Sharpless laboratory, synthetic chemists started to envision click reactions as the preferred choice of synthetic methodology employed to create new functions. This brief perspective will summarize research performed in our laboratories with the classic Cu(I)-catalyzed azide-alkyne click (CuAAC) reaction elaborated by Meldal and Sharpless, with the thio-bromo click (TBC) and with the less-used, irreversible TERminator Multifunctional INItiator (TERMINI) dual click (TBC) reactions, the last two elaborated in our laboratory. These click reactions will be used to assemble, by accelerated modular-orthogonal methodologies, complex macromolecules and self-organizations of biological relevance. Self-assembling amphiphilic Janus dendrimers and Janus glycodendrimers together with their biological membrane mimics known as dendrimersomes and glycodendrimersomes as well as simple methodologies to assemble macromolecules with perfect and complex architecture such as dendrimers from commercial monomers and building blocks will be discussed. This perspective is dedicated to the 75th anniversary of Professor Bogdan C. Simionescu, the son of my (VP) Ph.D. mentor, Professor Cristofor I. Simionescu, who as his father, took both science and science administration in his hands, and dedicated his life to handling them in a tandem way, to their best. Full article

Amphiphilic Janus dendrimers are arrangements containing both hydrophilic and hydrophobic units, capable of forming ordered aggregates by intermolecular noncovalent interactions between the dendrimer units. Compared to conventional dendrimers, these molecular self-assemblies possess particular and effective attributes i.e., the presence of different terminal groups, essential to design new elaborated materials. The present review will focus on the pharmaceutical and biomedical application of amphiphilic Janus dendrimers. Important information for the development of novel optimized pharmaceutical formulations, such as structural classification, synthetic pathways, properties and applications, will offer the complete characterization of this type of Janus dendrimers. This work will constitute an up-to-date background for dendrimer specialists involved in designing amphiphilic Janus dendrimer-based nanomaterials for future innovations in this promising field. Full article

The formulation of nanoscale systems with well-defined sizes and shapes is of great interest in applications such as drug and gene delivery, diagnostics and imaging. Dendrimers are polymers that have attracted interest due to their size, shape, branching length, amine density, and surface functionalities. These unique characteristics of dendrimers set them apart from other polymers, their ability to modify nanoparticles (NPs) for biomedical applications. Dendrimers are spherical with multiple layers over their central core, each representing a generation. Their amphiphilic nature and hollow structure allow for the incorporation of multiple drugs or genes, in addition to enabling easy surface modification with cellular receptor-targeting moieties to ensure site-specific delivery of therapeutics. Dendrimers are employed in chemotherapeutic applications for the delivery of anticancer drugs. There are many inorganic NPs currently being investigated for cancer therapy, each with their own unique biological, chemical, and physical properties. To favor biomedical applications, inorganic NPs require suitable polymers to ensure stability, biodegradability and target specificity. The success of dendrimers is dependent on their unique structure, good bioavailability and stability. In this review, we describe the properties of dendrimers and their use as modifiers of inorganic NPs for enhanced therapeutic delivery. Herein, we review the significant developments in this area from 2015 to 2022. Databases including Web of Science, Scopus, Google Scholar, Science Direct, BioMed Central (BMC), and PubMed were searched for articles using dendrimers, inorganic nanoparticles and cancer as keywords. Full article

Hydrogels are hydrophilic, three-dimensional networks able to imprison large amounts of water and are largely used in pharmaceutical formulations. Hydrogels are frequently obtained from hydrophilic polymers, either natural, biohybrid, or synthetic. Owing to their peculiar structure, dendrimers can be considered prospective building blocks for hydrogel networks. This review gathers the use of different types of amphiphilic dendritic structures able to generate physical hydrogels alone. Such dendritic structures comprise dendrimers, Janus dendrimers, and dendrons. The first part concerns different types of positively charged phosphorus dendrimers used to generate hydrogels, which are also suitable to form fibers, and for encapsulating diverse substances, or forming complexes with genetic materials for their slow delivery. The second part concerns PAMAM dendrimers functionalized with collagen mimetics. The third part concerns amphiphilic Janus dendrimers, whereas the fourth part displays different types of amphiphilic dendrons and their use, in particular in the fields of materials and drug delivery. Full article

Background: Due to resistance to conventional therapy, a blood–brain barrier that results in poor drug delivery, and a high potential for metastasis, glioblastoma (GBM) presents a great medical challenge. Since the repertoire of the possible therapies is very limited, novel therapeutic strategies require new drugs as well as new approaches. The multiple roles played by L-tryptophan (Trp) in tumorigenesis of GBM and the previously found antiproliferative properties of Trp-bearing dendrimers against this malignancy prompted us to design novel polyfunctional peptide-based dendrimers covalently attached to N¹-alkyl tryptophan (Trp) residues. Their antiproliferative properties against GBM and normal human astrocytes (NHA) and their antioxidant potential were tested. Methods: Two groups of amphiphilic peptide dendrimers terminated with N¹-butyl and N¹-aminopentane tryptophan were designed. The influence of dendrimers on viability of NHA and human GBM cell lines, displaying different genetic backgrounds and tumorigenic potentials, was determined by the MTT test. The influence of compounds on the clonogenic potential of GBM cells was assessed by colony-formation assay. Dendrimers were tested for radical scavenging potency as well as redox capability (DPPH, ABTS, and FRAP models). Results: Several peptide dendrimers functionalized with N¹-alkyl-tryptophan at 5 µM concentration exhibited high selectivity towards GBM cells retaining 85–95% viable NHA cells while killing cancer cells. In both the MTT and colony-formation assays, compounds 21 (functionalized with N¹-butyl-Trp and (+)8 charged) and 25 (functionalized with N¹-aminopentane-Trp and (+)12 charged) showed the most promise for their development into anticancer drugs. According to ABTS, DPPH, and FRAP antioxidant tests, dendrimers functionalized with N¹-alkylated Trp expressed higher ROS-scavenging capacity (ABTS and DPPH) than those with unsubstituted Trp. Conclusions: Peptide dendrimers functionalized with N¹-alkyl-tryptophan showed varying toxicity to NHA, while all were toxic to GBM cells. Based on their activity towards inhibition of GBM viability and relatively mild effect on NHA cells the most advantageous were derivatives 21 and 25 with the respective di-dodecyl and dodecyl residue located at the C-terminus. As expected, peptide dendrimers functionalized with N¹-alkyl-tryptophan expressed higher scavenging potency against ROS than dendrimers with unsubstituted tryptophan. Full article

Multidrug resistance (MDR) observed in tumors significantly hinders the efficacy of chemotherapy. Downregulation of efflux proteins, such as P-glycoprotein (P-gp), using small interfering RNA (siRNA) can be an effective way to minimize the resistance in tumors. In this study, monoclonal antibody 2C5 (mAb 2C5)-PEG_7k-DOPE conjugates were post-inserted into the mixed dendrimer micelles containing generation 4 (G4) polyamidoamine (PAMAM)-PEG_2k-DOPE and PEG_5k-DOPE. The inherent amphiphilic nature of DOPE conjugates causes the copolymers to self-assemble to form a micelle, which can encapsulate hydrophobic chemotherapeutic drugs in its core. The siRNA electrostatically binds to the cationic charges on the G4 PAMAM dendrimer. The tumor-specific mAb 2C5 on the surface of these nano-preparations resulted in improved tumor targeting. This active targeting to tumors can cause increase in the drug and siRNA accumulation at the tumor site, and thereby minimizing the off-target effects. The micelles were shown to have higher cellular association and effectiveness in vitro. The immunomicelle preparation was also tested for cytotoxicity in breast (MDA-MB-231) and ovarian (SKOV-3TR) MDR cancer cell lines. Full article

Liposomes with adjuvant properties are utilized to carry biomolecules, such as proteins, that are often sensitive to the stressful conditions of liposomal preparation processes. The aim of the present study is to use the aqueous heat method for the preparation of polymer-grafted hybrid liposomes without any additional technique for size reduction. Towards this scope, liposomes were prepared through the combination of two different lipids with adjuvant properties, namely dimethyldioctadecylammonium (DDA) and D-(+)-trehalose 6,6′-dibehenate (TDB) and the amphiphilic block copolymer poly(2-(dimethylamino)ethyl methacrylate)-b-poly(lauryl methacrylate) (PLMA-b-PDMAEMA). For comparison purposes, PAMAM dendrimer generation 4 (PAMAM G4) was also used. Preformulation studies were carried out by differential scanning calorimetry (DSC). The physicochemical characteristics of the prepared hybrid liposomes were evaluated by light scattering and their morphology was evaluated by cryo-TEM. Subsequently, in vitro nanotoxicity studies were performed. Protein-loading studies with bovine serum albumin were carried out to evaluate their encapsulation efficiency. According to the results, PDMAEMA-b-PLMA was successfully incorporated in the lipid bilayer, providing improved physicochemical and morphological characteristics and the ability to carry higher cargos of protein, compared to pure DDA:TDB liposomes, without affecting the biocompatibility profile. In conclusion, the aqueous heat method can be applied in polymer-grafted hybrid liposomes for protein delivery without further size-reduction processes. Full article

Despite being a mainstay of clinical cancer treatment, chemotherapy is limited by its severe side effects and inherent or acquired drug resistance. Nanotechnology-based drug-delivery systems are widely expected to bring new hope for cancer therapy. These systems exploit the ability of nanomaterials to accumulate and deliver anticancer drugs at the tumor site via the enhanced permeability and retention effect. Here, we established a novel drug-delivery nanosystem based on amphiphilic peptide dendrimers (AmPDs) composed of a hydrophobic alkyl chain and a hydrophilic polylysine dendron with different generations (AmPD KK₂ and AmPD KK₂K₄). These AmPDs assembled into nanoassemblies for efficient encapsulation of the anti-cancer drug doxorubicin (DOX). The AmPDs/DOX nanoformulations improved the intracellular uptake and accumulation of DOX in drug-resistant breast cancer cells and increased permeation in 3D multicellular tumor spheroids in comparison with free DOX. Thus, they exerted effective anticancer activity while circumventing drug resistance in 2D and 3D breast cancer models. Interestingly, AmPD KK₂ bearing a smaller peptide dendron encapsulated DOX to form more stable nanoparticles than AmPD KK₂K₄ bearing a larger peptide dendron, resulting in better cellular uptake, penetration, and anti-proliferative activity. This may be because AmPD KK₂ maintains a better balance between hydrophobicity and hydrophilicity to achieve optimal self-assembly, thereby facilitating more stable drug encapsulation and efficient drug release. Together, our study provides a promising perspective on the design of the safe and efficient cancer drug-delivery nanosystems based on the self-assembling amphiphilic peptide dendrimer. Full article