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.

Modern medicine continues to struggle against antibiotic-resistant bacterial pathogens. Among the pathogens of critical concerns are the multidrug-resistant (MDR) Pseudomonas aeruginosa, Staphylococcus aureus, and Klebsiella pneumoniae. These pathogens are major causes of nosocomial infections among immunocompromised individuals, involving major organs such as lung, skin, spleen, kidney, liver, and bloodstream. Therefore, novel approaches are direly needed. Recently, we developed an amphiphilic dendrimer DDC18-8A exhibiting high antibacterial and antibiofilm efficacy in vitro. DDC18-8A is composed of a long hydrophobic alkyl chain and a small hydrophilic poly(amidoamine) dendron bearing amine terminals, exerting its antibacterial activity by attaching and inserting itself into bacterial membranes to trigger cell lysis. Here, we examined the pharmacokinetics and in vivo toxicity as well as the antibacterial efficacy of DDC18-8A in mouse models of human infectious diseases. Remarkably, DDC18-8A significantly reduced the bacterial burden in mouse models of acute pneumonia and bacteremia by P. aeruginosa, methicillin-resistant S. aureus (MRSA), and carbapenem-resistant K. pneumoniae and neutropenic soft tissue infection by P. aeruginosa and MRSA. Most importantly, DDC18-8A outperformed pathogen-specific antibiotics against all three pathogens by achieving a similar bacterial clearance at 10-fold lower therapeutic concentrations. In addition, it showed superior stability and biodistribution in vivo, with excellent safety profiles yet without any observable abnormalities in histopathological analysis of major organs, blood serum biochemistry, and hematology. Collectively, we provide strong evidence that DDC18-8A is a promising alternative to the currently prescribed antibiotics in addressing challenges associated with nosocomial infections by MDR pathogens.

Two clinically approved anticancer drugs targeting BRAF in melanoma patients - dabrafenib (DAB) and vemurafenib (VEM) - have been successfully encapsulated into nanomicelles formed upon self-assembly of an amphiphilic dendrimer AD based on two C18 aliphatic chains and a G2 PAMAM head. The process resulted in the formation of well-defined (∼10 nm) core-shell nanomicelles (NMs) with excellent encapsulation efficiency (∼70% for DAB and ∼60% for VEM) and good drug loading capacity (∼27% and ∼24% for DAB and VEM, respectively). Dynamic light scattering (DLS), transmission electron microscopy (TEM), small-angle x-ray scattering (SAXS), nuclear magnetic resonance (NMR), isothermal titration calorimetry (ITC), and molecular simulation (MS) experiments were used, respectively, to determine the size and structure of the empty and drug-loaded nanomicelles (DLNMs), along with the interactions between the NMs and their cargoes. The in vitro release data revealed profiles governed by Fickian diffusion; moreover, for both anticancer molecules, an acidic environment (pH = 5.0) facilitated drug release with respect to physiological pH conditions (pH = 7.4). Finally, both DAB- and VEM-loaded NMs elicited enhanced response with respect to free drug treatments in 4 different melanoma cell lines.

UNASSIGNED: Gemcitabine is the first line and the gold standard drug for pancreatic cancer. However, the anticancer efficacy is severely limited by its instability and poor cellular uptake. To enhance the clinical efficacy of gemcitabine, we constructed a novel nanodrug delivery system based on amphiphilic dendrimers and aliphatic gemcitabine prodrug.
UNASSIGNED: An aliphatic gemcitabine prodrug and a small amphiphilic dendrimer were synthesized and characterized by high resolution mass spectrometry (HRMS) as well as nuclear magnetic resonance (NMR). Then the aliphatic gemcitabine prodrug was encapsulated into the small amphiphilic dendrimer by film dispersion method, resulting in a novel nanodrug delivery system. Subsequently, the size, morphology, drug loading, stability, drug release profiles, cell uptake, toxicity, the anticancer activity and in vivo distribution of the new developed gemcitabine delivery system were systematically evaluated by different technical methods, including transmission electron microscopy (TEM), dynamic light-scattering (DLS), ultraviolet spectrophotometer, flow cytometry, in vivo imaging system etc.
UNASSIGNED: We developed a novel nanodrug delivery system of gemcitabine using amphiphilic dendrimer. This dendrimer-based gemcitabine nanoformulation reported here possess a high drug loading of 33%. With the features of small size, stable formulation and pH-responsive drug release, the obtained gemcitabine nanoformulation could effectively accumulate in tumor site and rapid uptake in cells. Finally, the gemcitabine nanoformulation displayed more potent anticancer activity compared to free gemcitabine both in vitro and in vivo. Moreover, the nanodrug displayed greatly reduced adverse effects and satisfactory biocompatibility.
UNASSIGNED: Benefiting the advantageous features of both amphiphilic dendrimers and nanotechnology-based drug delivery, this gemcitabine nanosystem constitutes a promising therapeutic candidate for pancreatic cancer treatment. This study also underlines the potential use of self-assembling amphiphilic dendrimer-based nanotechnology for improving drug efficacy as well as reducing drug toxicity.

The increased threat of bacterial resistance against conventional antibiotics has warranted the need for development of membrane targeting antibacterial agents. Several self-assembled cationic amphiphiles with different supramolecular structures have been reported in recent years for potent antibacterial activity with increased specificity. In this study, we describe the self-assembly and antibacterial activity of four lower generation poly(aryl ether)-based amphiphilic dendrimers (AD-1, AD-2, AD-3, and AD-4) containing terminal amine (PAMAM-based), ester, and hydrazide functional groups with varied hydrophobicity. Among the four dendrimers under study, the amine-terminated dendrimer (AD-1) displayed potent antibacterial activity. The ratio of surface cationic charge to hydrophobicity had a significant effect on the antibacterial activity, where AD-3 dendrimer with increased surface cationic charges exhibited a higher minimum inhibitory concentration (MIC) than AD-1. AD-2 (ester terminated) and AD-4 (hydrazide terminated) dendrimers did not show any bactericidal activity. The amphiphilic dendrimer-bacteria interactions, further validated by binding studies, also showed significant changes in bacterial morphology, effective membrane permeation, and depolarization by AD-1 in comparison with AD-3. Molecular dynamics simulations of AD-1 and AD-3 on bacterial membrane patches further corroborated the experimental findings. The structural conformation of AD-1 dendrimer facilitated increased membrane interaction compared to AD-3 dendrimer. AD-1 also displayed selectivity to bacterial membranes over fibroblast cells (4× MIC), corroborating the significance of an optimal hydrophobicity for potent antibacterial activity with no cytotoxicity. The self-assembled (poly(aryl ether)-PAMAM-based) dendrimer (AD-1) also exhibited potent antibacterial activity in comparison with conventional higher generation dendrimers, establishing the implication of self-assembly for bactericidal activity. Moreover, the detailed mechanistic study reveals that optimal tuning of the hydrophobicity of amphiphilic dendrimers plays a crucial role in membrane disruption of bacteria. We believe that this study will provide valuable insights into the design strategies of amphiphilic dendrimers as antibacterial agents for efficient membrane disruption.

Although stimuli-responsive release systems have attracted great attention in medical applications, there has been no attempt at \"precise\" deep profile control based on such systems, which is greatly need to improve oil recovery. With this in mind, we provided a facile and simple strategy to prepare stimuli-responsive composite capsules of amphiphilic dendrimers-poly(styrene sulfonic acid) sodium/halloysite nanotubes (HNTs) via layer-by-layer (LbL) self-assembly technique, controlling the release crosslinking agent methenamine under different pH or salinity conditions. The release time of methenamine encapsulated in multilayer shells is about 40 h, which can be prolonged with the introduction of salt or shortened via the addition of acid, which accordingly induces the gelation of polyacrylamide (PAM) solutions, taking from a few hours to a dozen days. This study provided a novel approach for controllable release of chemical agents and controllable crosslinking of deep profiles in many application fields.

Aim: Alterations of microglia, the brain-resident macrophages, are associated with numerous brain pathologies. Genetic manipulation of microglia in diseases using small interfering RNA (siRNA) is hampered by the lack of safe and efficient siRNA delivery methods. We assessed the amphiphilic dendrimer (AD) for functional siRNA delivery and gene knockdown in primary microglia. Materials & methods: We characterized the ability of AD to form nanoparticles with siRNA, and studied their size, surface potential, cell uptake and gene silencing in rodent microglia. Results: AD effectively delivered siRNA to primary microglia and decreased target gene and protein expression, leading to transcriptomic changes without affecting basal microglial functions. Conclusion: The dendrimer AD promises to be an innocuous carrier for siRNA delivery into microglia.

Combination cancer therapy has attracted considerable attention due to its enhanced antitumor efficacy and reduced toxicity granted by synergistic effects over monotherapy. The application of nanotechnology is expected to achieve coencapsulation of multiple anticancer agents with enhanced therapeutic efficacy. Herein, a unique nanomicelle based on amphiphilic dendrimer (AmD) consisting of a hydrophilic polyamidoamine dendritic shell and a hydrophobic polylactide core is developed for effectively loading and shuttling 5-fluorouracil (5-Fu) and doxorubicin (Dox). The yielded drug-encapsulated dendritic nanomicelle (5-Fu/Dox-DNM) has a modest average size of 68.6 ± 3.3 nm and shows pH-sensitive drug release manner. The parallel activity of 5-Fu and Dox show synergistic anticancer efficacy. The IC50 value of 5-Fu/Dox-DNM toward human breast cancer (MDA-MB-231) cells was 0.25 μg/mL, presenting an 11.2-fold and 6.1-fold increase in cytotoxicity compared to Dox-DNM and 5-Fu-DNM, respectively. Furthermore, 5-Fu/Dox-DNM significantly inhibits the progression of tumor growth in the MDA-MB-231 xenograft tumor mice model. In conclusion, we have demonstrated that our AmD-based combination therapeutic system has promising potential to open an avenue for coencapsulation of multiple chemotherapeutic agents to promote superior anticancer effect.