An experimentally-informed coarse-grained model is presented to probe the self-assembly of multiple types of charged nanoparticles in a one-pot mixture in the presence of oppositely charged linkers across a broad range of nanoparticle charge and ionic strength of the solution. The model is applied to study the self-assembly of negatively-charged bacteriophage P22 virus-like particles (VLPs) of different types, with each type comprising VLPs of a distinct surface charge, in the presence of positively-charged polyamidoamine (PAMAM) generation-6 (G6) dendrimers. The model accurately captures the self-assembly of one-component systems, including the assembly states of the highest-charged P22 variant that were inaccessible with earlier models, revealing that P22 VLPs assemble into ordered arrays below a threshold ionic strength that increases with increasing variant charge, consistent with experiments. Molecular dynamics simulations of two, three, and four-component mixtures of P22 VLPs show that changing the ionic strength gradually over the range of well separated threshold ionic strengths via dialysis generates hierarchical assembly of ordered multilayered core-shell structures, with each layer comprising VLPs of a single variant type. A quick decrease in the ionic strength via rapid dilution leads to amorphous aggregates with a mixed composition of different variants. The mechanisms driving the VLPs into different macrostructures are explored by examining the bound and bridging dendrimers associated with the different types of VLPs. Simulation findings are consistent with experiments and establish salt dialysis as a simple and versatile strategy to engineer multilayered and ordered structures via a single-pot synthesis of multiple types of nanoscale building blocks.

The hydrophilic character and the protection against pathogen proliferation are the most pivotal characteristics of leathers intended for medical purposes. To achieve these goals, dispersions of TiO2 particles incorporating three different formulations of biomimetically synthesized silica xerogels were tested. Emphasis has been given to the role of single and dual solvents employed. Microbiocide capability was induced by benzalkonium chloride along with silver nanoparticles. Particular emphasis should be given to hyperbranched poly(ethylene imine) multifunctional roles. Spontaneous mineralization of silver ions is realized in the dendritic cavities. The same polymer acts as a matrix that interacts with the hydrogen bonding network of orthosilicic acid directing and facilitating gel formation. Furthermore, it contributes to both hydrophilicity and antimicrobial properties. Gel formation and subsequent drying occur in the pores of the impregnated TiO2 substrate. The resistance of the leathers to fungal and bacterial infections and biofilm formation was assessed against Klebsiella Pneumoniae, Escherichia coli, Pseudomonas aeruginosa, Enterococcus faecalis, Staphylococcus aureus, and Candida albicans. The affinity to water was proved by the contact angle method. The proposed treatment is a prospective environmentally friendly replacement to the standard finishing process of medical leathers.

Antimicrobial resistance (AMR) represents a critical global health challenge, driving the need for innovative therapeutic strategies. This study introduces self-assembled nanoparticles based on fourth-generation polyamidoamine (PAMAM-G4) dendrimers and Phloxine B (PhB), forming G4-PhB nanoparticles as an advanced platform for antimicrobial photodynamic therapy (aPDT). The optimal dendrimer:dye molar ratio was determined through dynamic light scattering (DLS) titration experiments, yielding a 1:15 G4:PhB ratio. The resulting G4-PhB nanoparticles were spherical, with a hydrodynamic diameter of 260 ± 15 nm, a narrow polydispersity index (PDI) of 0.264 ± 0.085, and a positive zeta potential of 8.71 ± 2.88 mV, indicating monodispersity and colloidal stability. These features were corroborated by morphological analyses using TEM and AFM. Cytotoxicity assays conducted on murine fibroblasts (3 T3 cell line), using MTT, neutral red uptake, and crystal violet staining revealed that G4-PhB nanoparticles are intrinsically non-toxic, contrasting with the EDTA-PhB complex, which exhibited significant cytotoxic effects. Antibacterial activity was evaluated against Staphylococcus aureus (SA) and Pseudomonas aeruginosa (PA). While free PhB demonstrated bactericidal effects exclusively against SA, the G4-PhB nanoparticles exhibited enhanced activity against both bacterial strains, notably overcoming the limitations of free PhB against PA. These findings highlight the versatility and effectiveness of G4-PhB nanoparticles as a biocompatible and non-invasive system for localized aPDT, with potential applications in wound healing for immunocompromised patients. This work provides a robust foundation for future research into dendrimer-based photosensitizers as innovative solutions to pressing biomedical challenges.

Bladder cancer is one of the most common malignant tumors of the urinary system globally. It is also one of the most expensive cancers to manage, due to the need for extensive treatment and follow-ups that often involve invasive and costly procedures. Although there have been some improvements in treatment options, the quality of life they offer has not improved at the same rate as other cancers. Therefore, there is an urgent need to find new alternatives to ease the burden of bladder cancer on patients. Recent discoveries have opened new avenues for the diagnosis and management of bladder cancer even though the clinical approach has largely remained the same for years. The decline in bladder cancer-specific mortality in regions that promote social awareness of risk factors and reduction of carcinogenic exposure demonstrates the effectiveness of such measures. New agents have been approved for patients who have undergone radical cystectomy after Bacillus Calmette-Guérin failure. Current best practices for diagnosing and treating bladder cancer are presented in this review. The review discusses radiation therapy, photodynamic therapy, gene therapy, chemotherapy, and nanomedicine in relation to non muscle-invasive cancers and muscle-invasive bladder cancers, as well as systemic treatments.

Essentially, the blood-brain barrier (BBB) serves as a line of demarcation between neural tissues and the bloodstream. A unique and protective characteristic of the blood-brain barrier is its ability to maintain cerebral homeostasis by regulating the flux of molecules and ions. The inability to uphold proper functioning in any of these constituents leads to the disruption of this specialized multicellular arrangement, consequently fostering neuroinflammation and neurodegeneration. Recent advancements in nanomedicine have been regarded as a promising avenue for improving the delivery of drugs to the central nervous system in the modern era. A major benefit of this innovation is that it allows drugs to accumulate selectively within the cerebral area by circumventing the blood-brain barrier. Although brain-targeted nanomedicines have demonstrated impressive achievements, certain limitations in targeting specificity still exist. In this examination, we scrutinize the distinctive physical and chemical attributes of nanoparticles (NPs) contributing to their facilitation in BBB traversal. We explore the various mechanisms governing NP passage over the BBB, encompassing paracellular conveyance, mediated transport, as well as adsorptive- and receptor-mediated transcytosis. The therapeutic success of NPs for the treatment of brain tumors has been extensively investigated through the use of various categories of NPs. Among these are polymeric nanoparticles, liposomes, solid lipid nanoparticles, dendrimers, metallic nanoparticles, quantum dots, and nanogels. The potential utility of nanoparticles goes beyond their ability to transport pharmaceuticals. They can serve as adept imaging contrast agents, capable of being linked with imaging probes. This will facilitate tumor visualization, delineate lesion boundaries and margins, and monitor drug delivery and treatment response. Versatile nanoparticles can be engineered to effectively target neoplastic lesions, serving dual roles in diagnostic imaging and therapeutic interventions. Subsequently, this discourse explores the constraints associated with nanoparticles in the context of treating brain tumors.

Ischemic stroke is a devastating neurovascular condition that occurs when cerebral tissue fails to receive an adequate supply of oxygen. Despite being a leading cause of death and disability worldwide, therapeutic interventions are currently limited. Polyamidoamine (PAMAM) dendrimers are nanomolecules commonly used in biomedical applications due to their ability to encapsulate small-molecules and improve their pharmacokinetic properties. Curcumin is known to have anti-inflammatory and antioxidant effects yet suffers from poor solubility and bioavailability. The purpose of this study is to investigate the efficacy of curcumin encapsulated in PAMAM dendrimers as a potential therapeutic treatment for ischemic stroke by studying post-stroke lesion size, astrocyte reactivity, and functional recovery in a rat model of cerebral ischemia.

Forty-eight male and female Sprague-Dawley rats (280-380 g) underwent either a 90-min middle cerebral artery occlusion (MCAo) or sham surgery before receiving one of four treatments: (1) Hanks' balanced salt solution (HBSS) control, (2) empty dendrimer control, (3) curcumin control, or (4) curcumin encapsulated in PAMAM dendrimer. Neurobehavioral outcomes were evaluated at 1-, 3-, 5-, and 7-day post-surgery, after which animals were euthanized on day 8 to assess infarct volume and GFAP immunoreactivity.

Animals that received formulations containing dendrimers (curcumin encapsulated in dendrimers or empty dendrimers) demonstrated significantly lower levels of GFAP immunoreactivity and improved functional recovery, including weight and neurobehavioral scores, compared to the formulations that did not contain dendrimers (curcumin and HBSS control). Additionally, the dendrimer-curcumin treatment group exhibited a significantly improved paw laterality index over the course of the study compared with the other three treatment groups.

Although the post-stroke administration of curcumin encapsulated in PAMAM dendrimers modulates the astrocytic response and promotes functional recovery following ischemic stroke in rats, its therapeutic benefits may be driven by PAMAM dendrimers as the empty dendrimer treatment group also showed significant improvements post-stroke. Further investigation regarding PAMAM dendrimers in treating neuroinflammatory conditions remains warranted.

The wound-healing process has usually been related to therapeutic agents with antioxidant properties. Among them, caffeic acid, a cinnamic acid derivative, stands out. However, the use of this natural product is affected by its bioavailability and half-life. Nowadays, different approaches are being taken to improve the above-mentioned characteristics, as many active surface groups are present in polyamidoamine (PAMAM) dendrimers; without the need for extra cross-linking agents, physical gels are created by interactions such as hydrogen bonds, van der Waals forces, or π-π interactions based on the modification of the surface. One of these is functionalization with dendrimers, such as the poly(amidoamine) (PAMAM) family. To evaluate the effectiveness of functionalizing caffeic acid with PAMAM dendrimers, the in vitro and in vivo wound-healing properties of gel-PAMAM G3 conjugated with caffeic acid (GPG3Ca) and its precursor, cinnamic acid (GPG3Cin), were studied. The results showed no cytotoxicity and wound-healing activity at a concentration of 20 μg/mL in HaCaT cells with the GPG3Ca. Additionally, the ability to activate molecular mediators of the healing process was evidenced. Furthermore, GPG3Ca potentiated the in vivo wound-healing process. The positive effects and lack of cytotoxicity at the used concentration of the synthesized GPG3Ca on the wound-healing process could position it as an effective agent for wound-healing treatment.

Taylor Dispersion Analysis (TDA) is explored to measure the hydrodynamic sizes of full and half generation PAMAM dendrimers up to generation 4.5 in various buffer solutions. A method was used to minimize the interaction between the capillary and cationic dendrimers. The effects of generation, surface functionality, pH and ionic strength on the hydrodynamic radii of PAMAM dendrimers were investigated. Our results show that TDA can accurately measure the sizes of PAMAM dendrimers with a relatively low standard deviation especially for half generations. It was found that the ionisation of functional groups at various pH values led to a conformational change due to electrostatic repulsion or back-folding of the branches. Furthermore, adding salt to a half-generation dendrimer (G4.5) can lead to a profound size change that is dependent on ionic strength. A 17% increase in the size of the G4.5 dendrimer was observed in a 1 M NaCl solution compared to that in a 0.1 M solution. Compared to dynamic light scattering, TDA is more reliable and tolerant to large particles in the solutions. The findings of this study indicate that TDA could serve as a viable alternative technique for assessing dendrimer size and conformation, as well as studying their binding behavior.

Lymph node metastasis is a critical indicator of cancer progression, profoundly affecting diagnosis, staging, and treatment decisions. This review article delves into the recent advancements in molecular imaging techniques for lymph nodes, which are pivotal for the early detection and staging of cancer. It provides detailed insights into how these techniques are used to visualize and quantify metastatic cancer cells, resident immune cells, and other molecular markers within lymph nodes. Furthermore, the review highlights the development of innovative, lymph node-targeted therapeutic strategies, which represent a significant shift towards more precise and effective cancer treatments. By examining cutting-edge research and emerging technologies, this review offers a comprehensive overview of the current and potential impact of lymph node-centric approaches on cancer diagnosis, staging, and therapy. Through its exploration of these topics, the review aims to illuminate the increasingly sophisticated landscape of cancer management strategies focused on lymph node assessment and intervention.

Amide-amine (PAMAM) dendrimers are biodegradable, non-immunogenic, genotoxic, and biocompatibible, which make them excellent materials for biological applications. In order to reduce the cytotoxicity of the designed branched molecules, a four-armed branched nucleus (B4) of PAMAM dendrimers as hyperbranched molecules was fused with polyhexamethylene biguanide (PHMB) (A2); hyperbranched polymeric biguanides (PAPBs) with a four-arm central core PAMAM structure were synthesized. The bactericidal and cell toxicity tests showed that PAPB had excellent bactericidal activity against both Gram-positive bacteria and Gram-negative, and the chemical binding of PHMB and PAMAM had synergistic effects. PAMAM reduced the toxicity of PAPB to 3T3 cells.

The escalating global threat of antibiotic resistance underscores the urgent need for innovative antimicrobial strategies. This review explores the cutting-edge applications of nanotechnology in combating bacterial infections, addressing a critical healthcare challenge. We critically assess the antimicrobial properties and mechanisms of diverse nanoparticle systems, including liposomes, polymeric micelles, solid lipid nanoparticles, dendrimers, zinc oxide, silver, and gold nanoparticles, as well as nanoencapsulated essential oils. These nanomaterials offer distinct advantages, such as enhanced drug delivery, improved bioavailability, and efficacy against antibiotic-resistant strains. Recent advancements in nanoparticle synthesis, functionalization, and their synergistic interactions with conventional antibiotics are highlighted. The review emphasizes biocompatibility considerations, stressing the need for rigorous safety assessments in nanomaterial applications. By synthesizing current knowledge and identifying emerging trends, this review provides crucial insights for researchers and clinicians aiming to leverage nanotechnology for next-generation antimicrobial therapies. The integration of nanotechnology represents a promising frontier in combating infectious diseases, underscoring the timeliness and imperative of this comprehensive analysis.

Background/Objectives: Doxorubicin (Dox) is an anticancer drug used in the treatment of a wide range of solid tumors; however, Dox causes systemic toxicity and irreversible cardiotoxicity. The design of a new nanosystem that allows for the control of Dox loading and delivery results is a powerful tool to control Dox release only in cancer cells. For this reason, supramolecular self-assembly was performed between a poly(amidoamine) (PAMAM) dendrimer decorated with four β-cyclodextrin (βCD) units (PAMAM-βCD) and an adamantane-hydrazone-doxorubicin (Ad-h-Dox) prodrug. Methods: The formation of inclusion complexes (ICs) between the prodrug and all the βCD cavities present on the surface of the PAMAM-βCD dendrimer was followed by 1H-NMR titration and corroborated by 2D NOESY experiments. A full characterization of the supramolecular assembly was performed in the solid state by thermal analysis (DSC/TGA) and scanning electron microscopy (SEM) and in solution by the DOSY NMR technique in D2O. Furthermore, the Dox release profiles from the PAMAM-βCD/Ad-h-Dox assembly at different pH values was studied by comparing the efficiency against a native βCD/Ad-h-Dox IC. Additionally, in vitro cytotoxic activity assays were performed for the nanocarrier alone and the two supramolecular assemblies in different carcinogenic cell lines. Results: The PAMAM-βCD/Ad-h-Dox assembly was adequately characterized, and the cytotoxic activity results demonstrate that the nanocarrier alone and its hydrolysis product are innocuous compared to the PAMAM-βCD/Ad-h-Dox nanocarrier that showed cytotoxicity equivalent to free Dox in the tested cancer cell lines. The in vitro drug release assays for the PAMAM-βCD/Ad-h-Dox system showed an acidic pH-dependent behavior and a prolonged profile of up to more than 72 h. Conclusions: The design of PAMAM-βCD/Ad-h-Dox consists of a new controlled and prolonged Dox release system for potential use in cancer treatment.

The management of inflammatory bowel disease (IBD) continues to pose significant challenges due to the absence of curative therapies and a high rate of recurrence. Therefore, it is imperative to explore novel approaches to enhance the efficacy of IBD therapy. Herein, a bioactive nanoparticulate s is tailored designed to achieve a "Pull-Push" approach for efficient and safe IBD treatment by integrating reactive oxygen species (ROS) scavenging (Pull) with anti-inflammatory agent delivery (Push) in the inflammatory microenvironment. The multifunctional nanomedicine, designated MON-PAMAM@SASP, is developed through the encapsulation of sulfasalazine (SASP), a widely utilized clinical drug for the treatment of IBD, within cationic diselenide-bridged mesoporous organosilica nanoparticles (MONs) that possess significant antioxidant properties. Herein, poly(amidoamine) (PAMAM) endows the original MONs with positive charge characteristics. The MON-PAMAM@SASP not only displays the remarkable capability of neutralizing ROS to ameliorates intestinal damage, but also achieves controllable release of SASP to mitigate intestinal inflammation. Consequently, this nanomedicine effectively mitigates IBD by colitis in mouse models, and our current research has not identified any significant drug toxicity. Beyond regulating inflammatory microenvironment in intestine, treatment with MON-PAMAM@SASP results in increased richness and restores intestinal microbiota homeostasis, thereby mitigating IBD to a certain extent. Together, our work provides a highly versatile "Pull-Push" approach for IBD management and encourages the development of similar nanomedicine to treating multiple inflammatory diseases of gastrointestinal tract.

Medical applications of iridium (III) complexes include their use as state-of-the-art theranostic agents - molecules that combine therapeutic and diagnostic functions into a single entity. These complexes offer a promising avenue in medical diagnostics, precision imaging at single-cell resolution and targeted anticancer therapy due to their unique properties. In this review we report a short summary of their application in medical diagnostics, imaging at single-cell level and targeted anticancer therapy. The exceptional photophysical properties of Iridium (III) complexes, including their brightness and photostability, make them excellent candidates for bioimaging. They can be used to image cellular processes and the microenvironment within single cells with unprecedented clarity, aiding in the understanding of disease mechanisms at the molecular level. Moreover the iridium (III) complexes can be designed to selectively target cancer cells,. Upon targeting, these complexes can act as photosensitizers for photodynamic therapy (PDT), generating reactive oxygen species (ROS) upon light activation to induce cell death. The integration of diagnostic and therapeutic capabilities in Iridium (III) complexes offers the potential for a holistic approach to cancer treatment, enabling not only the precise eradication of cancer cells but also the real-time monitoring of treatment efficacy and disease progression. This aligns with the goals of personalized medicine, offering hope for more effective and less invasive cancer treatment strategies.

Poly(amidoamine) dendrimers have been widely investigated as potential nanomaterials that can enhance the skin permeation of topically applied drugs. This article reviews the studies that have used dendrimers as penetration enhancers and examines the mechanisms by which enhancement is claimed.

A wide range of studies have demonstrated that, in certain circumstances and for certain drugs, the incorporation of dendrimers into a topically applied formulation can significantly increase the amount of drug passing into and through the skin. In some cases, dendrimers offered little or no enhancement of skin permeation, suggesting that the drug-dendrimer interaction and the selection of a specific dendrimer were central to ensuring optimal enhancement of skin permeation. Significant interactions between dendrimers and other formulation components were also reported in some cases.

Dendrimers offer substantial potential for enhancing drug delivery into and across the skin, putatively by mechanisms that include occlusion and changes to surface tension. However, most of these studies are conducted in vitro and limited progress has been made beyond such laboratory studies, some of which are conducted using membranes of limited relevance to humans, such as rodent skin. Thus, the outcomes and claims of such studies should be treated with caution.

Poly(amidoamine) dendrimer (PAMAM)/carbon quantum dot (CQD) nanohybrids are promising candidates for many biomedical applications, including drug delivery. Effectively designing a hybrid nanocarrier requires a deep understanding of the interactions of the hybrid nanoparticle with the drug to ensure drug stability and therapeutic efficiency. In this study, we utilized fully atomistic molecular dynamics (MD) simulations to investigate the adsorption behavior of a doxorubicin (DOX) anticancer drug onto a zwitterion/PAMAM/CQD hybrid nanocarrier. The hybrid nanoparticles were composed of CQD, at two oxidation levels, grafted with PAMAM dendrimers of generation 3 (G3) or 4 (G4) decorated with zwitterion monomers. Our work reveals that the generation of the grafted dendrimer was the primary determinant of efficient adsorption of DOX, unlike the oxidation level of CQD or dendrimer surface chemistry. After grafting, the G4 dendrimers assume a more stretched conformation compared to the G3 dendrimers. This allowed DOX molecules to penetrate inside the dendritic cavities of G4 dendrimers, resulting in enhanced drug protection. The hydrophobic interaction, between the aromatic structure of DOX molecules and the nonpolar parts of dendrimers, has been proven to play a crucial role in mediating the adsorption of drug molecules. These findings provide valuable insights to assist in the design of a zwitterion/PAMAM/CQD hybrid nanoplatform for drug delivery applications.

One of the intensively developed tools for cancer therapy is drug-releasing matrices. Polyamidoamine dendrimers (PAMAM) are commonly used as nanoparticles to increase the solubility, stability and retention of drugs in the human body. Most often, drugs are encapsulated in PAMAM cavities or covalently attached to their surface. However, there are no data on the use of PAMAM dendrimers as a component of porous matrices based on polyurethane foams for the controlled release of drugs and biologically active substances. Therefore, in this work, porous materials based on polyurethane foam with incorporated third-generation poly(amidoamine) dendrimers (PAMAM G3) were synthesized and characterized. Density, water uptake and morphology of foams were examined with SEM and XPS. The PAMAM was liquefied with polyether polyol (G441) and reacted with polymeric 4,4'-diphenylmethane diisocyanate (pMDI) in the presence of silicone, water and a catalyst to obtain foam (PF1). In selected compositions, the castor oil was added (PF2). Analogs without PAMAM G3 were also synthesized (F1 and F2, respectively). An SEM analysis of foams showed that they are composed of thin ribs/walls forming an interconnected network containing hollow bubbles/pores and showing some irregularities in the structure. Foam from a G3:G441:CO (PF2) composition is characterized by a more regular structure than the foam from the composition without castor oil. The encapsulation efficiency of drugs determined by the XPS method shows that it varies depending on the matrix and the drug and ranges from several to a dozen mass percent. In vitro biological studies with direct contact and extract assays indicated that the F2 matrix was highly biocompatible. Significant toxicity of dendrimeric matrices PF1 and PF2 containing 50% of PAMAM G3 was higher against human squamous carcinoma cells than human immortalized keratinocytes. The ability of the matrices to immobilize drugs was demonstrated in the example of perspective (Nimesulide, 8-Methoxypsolarene) or approved anticancer drugs (Doxorubicin-DOX, 5-Aminolevulinic acid). Release into the culture medium and penetration of DOX into the tested SCC-15 and HaCaT cells were also proved. The results show that further modification of the obtained matrices may lead to their use as drug delivery systems, e.g., for anticancer therapy.

The regeneration of demineralized enamel holds great significance in the treatment of dental caries. Amelogenin (Ame), an essential protein for mediating natural enamel growth, is no longer secreted after enamel has fully matured in childhood. Although biomimetic mineralization based on peptides or proteins has made significant progress, easily accessible, low-cost, biocompatible and highly effective Ame mimics are still lacking. Herein, we construct a series of amphiphilic branched polypeptides (CAMPs) by facile coupling of the Ame's C-terminal segment and poly(γ-benzyl-L-glutamate), which serves to simulate the Ame's hydrophobic N-terminal segment. Among them, CAMP15 is the best biomimetic mineralization template with great self-assembly performance to guide the oriented crystallization of hydroxyapatite and is capable of inhibiting the adhesion of Streptococcus mutans and Staphylococcus aureus on the enamel surfaces. This work highlights the potential application of amphiphilic branched polypeptide as Ame mimics in repairing defected enamel, providing a promising strategy for prevention and treatment of dental caries.

White spot lesions (WSLs) and demineralized enamel surfaces are common dental issues that can lead to further complications if untreated. The potential of various remineralizing agents has been extensively studied, but the efficacy of polyamidoamine (PAMAM) dendrimers in promoting enamel remineralization remains to be fully elucidated. This systematic review aims to evaluate the remineralizing potential of PAMAM on WSLs and demineralized enamel surfaces. To identify relevant studies, a comprehensive literature search was conducted across multiple databases, including PubMed, Scopus, and Cochrane Library. Inclusion criteria comprised in vitro and in vivo studies that assessed the effects of PAMAM on WSLs or demineralized enamel. Data extraction and quality assessment were performed independently by two reviewers. The primary outcomes measured were changes in enamel microhardness, surface morphology, and mineral content. Five studies met the inclusion criteria, comprising in vitro studies. The results indicated that PAMAM demonstrated a significant remineralizing effect on demineralized enamel surfaces, as evidenced by increased microhardness and improved surface morphology. The studies varied in their methodological approaches but collectively supported the potential of PAMAM in enamel remineralization. PAMAM dendrimers exhibit promising remineralizing properties for treating WSLs and demineralized enamel surfaces.

Dendrimers are employed as functional elements in contrast agents and are proposed as nontoxic vehicles for drug delivery. Toxicity is a property that is to be evaluated for this novel class of bionanomaterials for in vivo applications. The current research is hampered due to the lack of structured data sets for toxicity studies for dendrimers. In this work, we have built a data set by curating literature for toxicity data and augmented it with structural and physicochemical features. We present a comprehensive, feature-rich database of dendrimer toxicity measured across various cell lines for prediction, design, and optimization studies. We have also explored novel computational approaches for predicting dendrimer cytotoxicity. We demonstrate superior outcomes for toxicity prediction using essential regression in the space of small data sets.

Dendrimers are potent nanocarriers in drug delivery systems because their structure can be precisely controlled. We previously reported that polyamidoamine (PAMAM) dendrimers that were modified with 1,2-cyclohexanedicarboxylic acid (CHex) and phenylalanine (Phe), PAMAM-CHex-Phe, exhibited an effective association with various immune cells, including T-cells. In this study, we synthesized various carboxy-terminal Phe-modified dendrimers with different linkers using phthalic acid and linear dicarboxylic acids to determine the association of these dendrimers with Jurkat cells, a T-cell model. PAMAM-n-hexyl-Phe demonstrated the highest association with Jurkat T-cells. In addition, dendri-graft polylysine (DGL) with CHex and Phe, DGL-CHex-Phe, was synthesized, and its association with Jurkat cells was investigated. The association of DGL-CHex-Phe with T-cells was higher than that of PAMAM-CHex-Phe. However, it was insoluble in water and thus it is unsuitable as a drug carrier. Model drugs, such as protoporphyrin IX and paclitaxel, were loaded onto these dendrimers, and the most model drug molecules could be loaded into PAMAM-CHex-Phe. PTX-loaded PAMAM-CHex-Phe exhibited cytotoxicity against Jurkat cells at a similar level to free PTX. These results suggest that PAMAM-CHex-Phe exhibited both efficient T-cell association and drug loading properties.

Herein, we isolated five natural alkaloids, iso-corydine (iso-CORY), corydine (CORY), sanguinarine (SAN), chelerythrine (CHE) and magnoflorine (MAG), from traditional medicinal herb Dicranostigma leptopodum (Maxim.) Fedde (whole herb) and elucidated their structures. Then we synthesised G5. NHAc-PBA as targeting dendrimer platform to encapsulate the alkaloids into G5. NHAc-PBA-alkaloid complexes, which demonstrated alkaloid-dependent positive zeta potential and hydrodynamic particle size. G5. NHAc-PBA-alkaloid complexes demonstrated obvious breast cancer MCF-7 cell targeting effect. Among the G5. NHAc-PBA-alkaloid complexes, G5.NHAc-PBA-CHE (IC50=13.66 μM) demonstrated the highest MCF-7 cell inhibition capability and G5.NHAc-PBA-MAG (IC50=24.63 μM) had equivalent inhibitory effects on cell proliferation that comparable to the level of free MAG (IC50=23.74 μM), which made them the potential breast cancer targeting formulation for chemotherapeutic application. This work successfully demonstrated a pharmaceutical research model of 'natural bioactive product isolation-drug formulation preparation-breast cancer cell targeting inhibition'.

The management of diabetes in a manner offering autonomous insulin therapy responsive to glucose-directed need, and moreover with a dosing schedule amenable to facile administration, remains an ongoing goal to improve the standard of care. While basal insulins with reduced dosing frequency, even once-weekly administration, are on the horizon, there is still no approved therapy that offers glucose-responsive insulin function. Herein, a nanoscale complex combining both electrostatic- and dynamic-covalent interactions between a synthetic dendrimer carrier and an insulin analogue modified with a high-affinity glucose-binding motif yields an injectable insulin depot affording both glucose-directed and long-lasting insulin availability. Following a single injection, it is even possible to control blood glucose for at least one week in diabetic swine subjected to daily oral glucose challenges. Measurements of serum insulin concentration in response to challenge show increases in insulin corresponding to elevated blood glucose levels, an uncommon finding even in preclinical work on glucose-responsive insulin. Accordingly, the subcutaneous nanocomplex that results from combining electrostatic- and dynamic-covalent interactions between a modified insulin and a synthetic dendrimer carrier affords a glucose-responsive insulin depot for week-long control following a single routine injection.

In recent years, various conventional formulations have been used for the treatment and/or management of ocular medical conditions. Diabetic retinopathy, a microvascular disease of the retina, remains the leading cause of visual disability in patients with diabetes. Currently, for treating diabetic retinopathy, only intraocular, intravitreal, periocular injections, and laser photocoagulation are widely used. Frequent administration of these drugs by injections may lead to serious complications, including retinal detachment and endophthalmitis. Although conventional ophthalmic formulations like eye drops, ointments, and suspensions are available globally, these formulations fail to achieve optimum drug therapeutic profile due to immediate nasolacrimal drainage, rapid tearing, and systemic tearing toxicity of the drugs. To achieve better therapeutic outcomes with prolonged release of the therapeutic agents, nano-drug delivery materials have been investigated. These nanocarriers include nanoparticles, solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), dendrimers, nanofibers, in-situ gel, vesicular carriers, niosomes, and mucoadhesive systems, among others. The nanocarriers carry the potential benefits of site-specific delivery and controlled and sustained drug release profile. In the present article, various nanomaterials explored for treating diabetic retinopathy are reviewed.

The application of hydrogels for anti-cancer drug delivery has garnered considerable interest in the medical field. Current cancer treatment approaches, such as chemotherapy and radiation therapy, often induce severe side effects, causing significant distress and substantial health complications to patients. Hydrogels present an appealing solution as they can be precisely injected into specific sites within the body, facilitating the sustainable release of encapsulated drugs. This localized treatment approach holds great potential for reducing toxicity levels and improving drug delivery efficacy. In this study we developed a hydrogel delivery system containing polyamidoamine (PAMAM) dendrimer and polyethylene glycol (PEG) for solubility enhancement and sustained delivery of hydrophobic anti-cancer drugs. The three selected model drugs, e.g. silibinin, camptothecin, and methotrexate, possess limited aqueous solubility and thus face restricted application. In the presence of vinyl sulfone functionalized PAMAM dendrimer at 45 mg/mL concentration, drug solubility is increased by 37-fold, 4-fold, and 10-fold for silibinin, camptothecin, and methotrexate, respectively. By further crosslinking of the functionalized PAMAM dendrimer and thiolated PEG, we successfully developed a fast-crosslinking hydrogel capable of encapsulating a significant payload of solubilized cancer drugs for sustained release. In water, the drug encapsulated hydrogels release 30%-80% of their loads in 1-4 days. MTT assays of J82 and MCF7 cells with various doses of drug encapsulated hydrogels reveal that cytotoxicity is observed for all three drugs on both J82 and MCF7 cell lines after 48 h. Notably, camptothecin exhibits higher cytotoxicity to both cell lines than silibinin and methotrexate, achieving up to 95% cell death at experimental conditions, despite its lower solubility. Our experiments provide evidence that the PAMAM dendrimer-mediated hydrogel system significantly improves the solubility of hydrophobic drugs and facilitates their sustained release. These findings position the system as a promising platform for controlled delivery of hydrophobic drugs for intratumoral cancer treatment.

Development of a nanoscale drug delivery system that can simultaneously exert efficient tumor therapeutic efficacy while creating the desired antitumor immune responses is still challenging. Herein, we report the use of a manganese dioxide (MnO2)-entrapping dendrimer nanocarrier to codeliver glucose oxidase (GOx) and cyclic GMP-AMP (cGAMP), an agonist of the stimulator of interferon genes (STING) for improved tumor chemodynamic/starvation/immune therapy. Methoxy poly(ethylene glycol) (mPEG)- and phenylboronic acid (PBA)-modified generation 5 (G5) poly(amidoamine) dendrimers were first synthesized and then entrapped with MnO2 nanoparticles (NPs) to generate the hybrid MnO2@G5-mPEG-PBA (MGPP) NPs. The created MGPP NPs with an MnO2 core size of 2.8 nm display efficient glutathione depletion ability, and a favorable Mn2+ release profile under a tumor microenvironment mimetic condition to enable Fenton-like reaction and T1-weighted magnetic resonance (MR) imaging. We show that the MGPP-mediated GOx delivery facilitates enhanced chemodynamic/starvation therapy of cancer cells in vitro, and further codelivery of cGAMP can effectively trigger immunogenic cell death (ICD) to strongly promote the maturation of dendritic cells. In a bilateral mouse colorectal tumor model, the dendrimer delivery nanosystem elicits a potent antitumor performance with a strong abscopal effect, greatly improving the overall mouse survival rate. Importantly, the dendrimer-mediated codelivery not only allows the coordination of Mn2+ with GOx and cGAMP for respective chemodynamic/starvation-triggered ICD and augmented STING activation to boost systemic antitumor immune responses, but also enables T1-weighted tumor MR imaging, potentially serving as a promising nanoplatform for enhanced antitumor therapy with desired immune responses.

Inorganic nanocrystals possess unique physicochemical properties compared to their bulk counterparts. Stabilizing agents are commonly used for the preparation of inorganic nanocrystals with controllable properties. Particularly, colloidal polymers have emerged as general and robust templates for in situ formation and confinement of inorganic nanocrystals. In addition to templating and stabilizing inorganic nanocrystals, colloidal polymers can tailor their physicochemical properties such as size, shape, structure, composition, surface chemistry, and so on. By incorporating functional groups into colloidal polymers, desired functions can be integrated with inorganic nanocrystals, advancing their potential applications. Here, recent advances in the colloidal polymer-templated formation of inorganic nanocrystals are reviewed. Seven types of colloidal polymers, including dendrimer, polymer micelle, stare-like block polymer, bottlebrush polymer, spherical polyelectrolyte brush, microgel, and single-chain nanoparticle, have been extensively applied for the synthesis of inorganic nanocrystals. Different strategies for the development of these colloidal polymer-templated inorganic nanocrystals are summarized. Then, their emerging applications in the fields of catalysis, biomedicine, solar cells, sensing, light-emitting diodes, and lithium-ion batteries are highlighted. Last, the remaining issues and future directions are discussed. This review will stimulate the development and application of colloidal polymer-templated inorganic nanocrystals.

Surface-modified PAMAM dendrimers have important applications in drug delivery, yet a gap remains about the role that surface functionalization plays on their cell internalization capacity. We examined the cell internalization kinetics of PAMAM dendrimers that were surface-modified with acetyl, folate and poly(ethylene glycol), as model functional groups differing in size, charge, and chemical functionality. Dendrimers with 25% functionalization were internalized by HEK cells, but with slower rates and lower maximum uptakes than the native dendrimer between 1-6 h of incubation. Dendrimers with 50% functionalization exhibited negligible internalization capacities at all incubation times. Molecular dynamics simulations revealed that the solvent accessibility of the cationic surface charges is a key factor affecting cell internalization, unlike the total charge, functionality or size of surface-modified PAMAM dendrimers. These findings provide valuable insights to assist the design of PAMAM-based systems for drug delivery applications.

The synthesis of a new family of ethylenediaminetetraacetic acid (EDTA) core dimers and G0 dendrimers end-capped with two and four β-cyclodextrin (βCD) moieties was performed by click-chemistry conjugation, varying the spacers attached to the core. The structure analyses were achieved in DMSO-d6 and the self-inclusion process was studied in D2O by 1H-NMR spectroscopy for all platforms. It was demonstrated that the interaction with adamantane carboxylic acid (AdCOOH) results in a guest-induced shift of the self-inclusion effect, demonstrating the full host ability of the βCD units in these new platforms without any influence of the spacer. The results of the quantitative size and water solubility measurements demonstrated the equivalence between the novel EDTA-βCD platforms and the classical PAMAM-βCD dendrimer. Finally, we determined the toxicity for all EDTA-βCD platforms in four different cell lines: two human breast cancer cells (MCF-7 and MDA-MB-231), human cervical adenocarcinoma cancer cells (HeLa), and human lung adenocarcinoma cells (SK-LU-1). The new EDTA-βCD carriers did not present any cytotoxicity in the tested cell lines, which showed that these new classes of platforms are promising candidates for drug delivery.

A new heterocyclic monomer is developed via simple Diels-Alder reaction which is reluctant to polymerize in dichloromethane (DCM) whereas undergoes facile polymerization in tetrahydrofuran with excellent control over molecular weight (Mn ) and dispersities (Đ) using Grubbs' third generation catalyst (G3). The deprotection of the tert-butoxycarbonyl group from the polymeric backbone yielded a water-soluble ring opening metathesis polymerization (ROMP) polymer easily. Moreover, in DCM this new monomer copolymerizes with 2,3-dihydrofuran under catalytic living ROMP conditions to give backbone degradable polymers. All the synthesized polymers are characterized by size exclusion chromatography (SEC) and nuclear magnetic resonance (NMR) spectroscopy. It is believed that this new route to water soluble ROMP homopolymers as well as the cost-effective and environmentally friendly route to degradable copolymers and block-copolymers could find applications in biomedicine in the near future.

Four leather substrates from different animals were treated by dispersions containing hydrophilic composite silica-hyperbranched poly(ethylene imine) xerogels. Antimicrobial activity was introduced by incorporating silver nanoparticles and/or benzalkonium chloride. The gel precursor solutions were also infused before gelation to titanium oxide powders typically employed for induction of self-cleaning properties. The dispersions from these biomimetically premade xerogels integrate environmentally friendly materials with short coating times. Scanning electron microscopy (SEM) provided information on the powder distribution onto the leathers. Substrate and coating composition were estimated by infrared spectroscopy (IR) and energy-dispersive X-ray spectroscopy (EDS). Surface hydrophilicity and water permeability were assessed by water-contact angle experiments. The diffusion of the leather's initial components and xerogel additives into the water were measured by Ultraviolet-Visible (UV-Vis) spectroscopy. Protection against GRAM- bacteria was tested for Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae against GRAM+ bacteria for Staphylococcus aureus and Enterococcus faecalis and against fungi for Candida albicans. Antibiofilm capacity experiments were performed against Staphylococcus aureus, Klebsiella pneumoniae, Enterococcus faecalis, and Candida albicans. The application of xerogel dispersions proved an adequate and economically feasible alternative to the direct gel formation into the substrate's pores for the preparation of leathers intended for medical uses.

Lymph nodes play a pivotal role in tumor progression as key components of the lymphatic system. However, the unique physiological structure of lymph nodes has traditionally constrained the drug delivery efficiency. Excitingly, nanomedicines have shown tremendous advantages in lymph node-specific delivery, enabling distinct recognition and diagnosis of lymph nodes, and hence laying the foundation for efficient tumor therapies. In this review, we comprehensively discuss the key factors affecting the specific enrichment of nanomedicines in lymph nodes, and systematically summarize nanomedicines for precise lymph node drug delivery and therapeutic application, including the lymphatic diagnosis and treatment nanodrugs and lymph node specific imaging and identification system. Notably, we delve into the critical challenges and considerations currently facing lymphatic nanomedicines, and futher propose effective strategies to address these issues. This review encapsulates recent findings, clinical applications, and future prospects for designing effective nanocarriers for lymphatic system targeting, with potential implications for improving cancer treatment strategies.

Polyphosphate (PolyP) is a polymer comprised of linear phosphate units connected by phosphate anhydride bonds. PolyP exists in a diverse range of eukaryotes and prokaryotes with varied chain lengths ranging from six to thousands of phosphate units. Upon activation, human platelets and neutrophils release short-chain PolyP, along with other components, to initiate the coagulation pathway. Long-chain PolyP derived from cellular or bacterial organelles exhibits higher proinflammatory and procoagulant effects compared to short-chain PolyP. Notably, PolyP has been identified as a low-hemorrhagic antithrombotic target since neutralizing plasma PolyP suppresses the thrombotic process without impairing the hemostatic functions. As an inorganic polymer without uniform steric configuration, PolyP is typically targeted by cationic polymers or recombinant polyphosphatases rather than conventional antibodies, small-molecule compounds, or peptides. Additionally, because of its procoagulant property, PolyP has been incorporated in wound-dressing materials to facilitate blood hemostasis. This review summarizes current studies on PolyP as a low-hemorrhagic antithrombotic target and the development of hemostatic materials based on PolyP.

Dendronized nanoparticles, also called nanoparticle-cored dendrimers, combine the advantages of nanoparticles and dendrimers. These very stable and polyvalent nanoparticles can be used for diverse applications. One such application is drug delivery, because the dendrons can enhance the density of the payload. In this report, we describe the design of multifunctional gold nanoparticles (AuNPs) coated with poly(propylene imine) (PPI) dendrons that contain both prostate cancer active targeting and chemotherapeutic drugs. The PPI dendron is a good candidate for the design of drug delivery vehicles because of its ability to induce a proton sponge effect that will enhance lysosomal escape and intracellular therapeutic delivery. The chemotherapeutic drug used is doxorubicin (DOX), and it was linked to the dendron through a hydrazone acid-sensitive bond. Subsequent acidification of the AuNP system to a pH of 4-5 resulted in the release of 140 DOX drugs per nanoparticles. In addition, the PPI dendron was conjugated via "click" chemistry to an EphA2-targeting antibody fragment that has been shown to target prostate cancer cells. In vitro cell viability assays revealed an IC50 of 0.9 nM for the targeted DOX-bearing AuNPs after 48 h incubation with PC3 cells. These results are very promising upon optimization of the system.

In vivo imaging has enabled impressive advances in biological research, both preclinical and clinical, and researchers have an arsenal of imaging methods available. Bioluminescence imaging is an advantageous method for in vivo studies that allows for the simple acquisition of images with low background signals. Researchers have increasingly been looking for ways to improve bioluminescent imaging for in vivo applications, which we sought to achieve by developing a bioluminescent probe that could specifically target cells of interest. We chose pancreatic ductal adenocarcinoma (PDAC) as the disease model because it is the most common type of pancreatic cancer and has an extremely low survival rate. We targeted the epidermal growth factor receptor (EGFR), which is frequently overexpressed in pancreatic cancer cells, using an EGFR-specific affibody to selectively identify PDAC cells and delivered a Gaussia luciferase (GLuc) bioluminescent protein for imaging by engineering a fusion protein with both the affibody and the bioluminescent protein. This fusion protein was then complexed with a G5-PAMAM dendrimer nanocarrier. The dendrimer was used to improve the protein stability in vivo and increase signal strength. Our targeted bioluminescent complex had an enhanced uptake into PDAC cells in vitro and localized to PDAC tumors in vivo in pancreatic cancer xenograft mice. The bioluminescent complexes could delineate the tumor shape, identify multiple masses, and locate metastases. Through this work, an EGFR-targeted bioluminescent-dendrimer complex enabled the straightforward identification and imaging of pancreatic cancer cells in vivo in preclinical models. This argues for the targeted nanocarrier-mediated delivery of bioluminescent proteins as a way to improve in vivo bioluminescent imaging.

High-throughput screening platforms are fundamental for the rapid and efficient processing of large amounts of experimental data. Parallelization and miniaturization of experiments are important for improving their cost-effectiveness. The development of miniaturized high-throughput screening platforms is essential in the fields of biotechnology, medicine, and pharmacology. Currently, most laboratories use 96- or 384-well microtiter plates for screening; however, they have disadvantages, such as high reagent and cell consumption, low throughput, and inability to avoid cross-contamination, which need to be further optimized. Droplet microarrays, as novel screening platforms, can effectively avoid these shortcomings. Here, the preparation method of the droplet microarray, method of adding compounds in parallel, and means to read the results are briefly described. Next, the latest research on droplet microarray platforms in biomedicine is presented, including their application in high-throughput culture, cell screening, high-throughput nucleic acid screening, drug development, and individualized medicine. Finally, the challenges and future trends in droplet microarray technology are summarized.

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.

Paper surface functionalization with polyamidoamine (PAMAM) dendrimers has been developed for increased sensitivity analysis of proteins by paper spray mass spectrometry (PS-MS). PAMAM is a branched polymeric compound with an ethylenediamine core linked to repeating PAMAM units that generates an outer surface rich in primary amines. These positively charged amine groups can interact electrostatically with negatively charged residues (e.g., aspartate, glutamate) on the protein surface. PAMAM inner amide moieties can also promote hydrogen bonding with protein surface oxygens, making PAMAM a useful material for protein extraction. PAMAM-functionalized PS-MS paper strips were used to extract proteins from biofluids, dipped in acetonitrile to remove unbound constituents, dried, and then measured with PS-MS. The use of this strategy was optimized and compared with unmodified paper strips. PAMAM-functionalized paper substrates provided sixfold greater sensitivity for albumin, 11-fold for hemoglobin, sevenfold for insulin, and twofold for lysozyme. The analytical performance of the functionalized paper substrate was evaluated through the analysis of albumin in urine, achieving linearity with R² > 0.99, LOD of 1.1 μg mL^-1, LOQ of 3.8 μg mL^-1, precision better than 10%, and relative recovery 70-83%. The method was applied to quantify urinary albumin from nine anonymous patient samples (concentrations ranged from 6.5 to 77.4 μg mL^-1), illustrating its potential for the diagnosis of microalbuminuria. These data demonstrate the utility of paper modification with the PAMAM dendrimer for sensitive PS-MS analysis of proteins, opening a path for further applications in clinical diagnosis through the analysis of disease-related proteins.