Nanoparticle-Mediated Multiple Modulation of Bone Microenvironment To Tackle Osteoarthritis.

Development of nanomedicines that can collaboratively scavenge reactive oxygen species (ROS) and inhibit inflammatory cytokines, along with osteogenesis promotion, is essential for efficient osteoarthritis (OA) treatment. Herein, we report the design of a ROS-responsive nanomedicine formulation based on fibronectin (FN)-coated polymer nanoparticles (NPs) loaded with azabisdimethylphoaphonate-terminated phosphorus dendrimers (G4-TBP). The constructed G4-TBP NPs-FN with a size of 268 nm are stable under physiological conditions, can be specifically taken up by macrophages through the FN-mediated targeting, and can be dissociated in the oxidative inflammatory microenvironment. The G4-TBP NPs-FN loaded with G4-TBP dendrimer having intrinsic anti-inflammatory property and FN having both anti-inflammatory and antioxidative properties display integrated functions of ROS scavenging, hypoxia attenuation, and macrophage M2 polarization, thus protecting macrophages from apoptosis and creating designed bone immune microenvironment for stem cell osteogenic differentiation. These characteristics of the G4-TBP NPs-FN lead to their effective treatment of an OA model in vivo to reduce pathological changes of joints including synovitis inhibition and cartilage matrix degradation and simultaneously promote osteogenic differentiation for bone repair. The developed nanomedicine formulation combining the advantages of both bioactive phosphorus dendrimers and FN to treat OA may be developed for immunomodulatory therapy of different inflammatory diseases.

Codelivery of CuS and DOX into Deep Tumors with Size and Charge-Switchable PAMAM Dendrimers for Chemo-photothermal Therapy.

Accurate targeting of therapeutic agents to specific tumor tissues, especially via deep tumor penetration, has been an effective strategy in cancer treatments. Here, we described a flexible nanoplatform, pH-responsive zwitterionic acylsulfonamide betaine-functionalized fourth-generation PAMAM dendrimers (G4-AB), which presented multiple advantages for chemo-photothermal therapy, including template synthesis of ultrasmall copper sulfide (CuS) nanoparticles and further encapsulation of doxorubicin (DOX) (G4-AB-DOX/CuS), long-circulating performance by a relatively large size and zwitterionic surface in a physiological environment, combined size shrinkage, and charge conversions via pH-responsive behavior in an acidic tumor microenvironment (TME). Accordingly, high tumor penetration and positive cell uptake for CuS and DOX have been determined, which triggered an excellent combination treatment under near-infrared irradiation in comparison to the monochemotherapy system and irresponsive chemo-photothermal system. Our study represented great promise in constructing multifunctional carriers for the effective delivery of photothermal nanoparticles and drugs in chemo-photothermal therapy.

Cationic amphiphilic dendrons with effective antibacterial performance.

Bacterial infections and antibiotic resistance have become a global healthcare crisis. Herein, we designed and synthesized a series of cationic amphiphilic dendrons with cationic dendrons and hydrophobic alkyl chains for potential antibacterial applications. Our results showed that the antimicrobial activities of the cationic amphiphilic dendrons were highly dependent upon the length of the hydrophobic alkyl chain, whereas the number of cationic charges was less important. Among these cationic amphiphilic dendrons, a prime candidate was identified, which possessed excellent antimicrobial activity against various pathogens (minimum inhibitory concentrations of 9, 3, and 3 µg mL-1 for Escherichia coli, Staphylococcus aureus, and methicillin-resistant Staphylococcus aureus, respectively). Scanning electron microscopy and fluorescence microscopy analyses showed that it could disrupt the integrity of a pathogen's membrane, leading to cell lysis and death. In addition, in vitro bacteria-killing kinetics showed that it had rapid bactericidal efficiency. It also had excellent antimicrobial activities against MRSA in vivo and promoted wound healing. In general, the synthesized cationic amphiphilic dendrons, which exhibited rapid and broad-spectrum bactericidal activity, may have great potential in antimicrobial applications.

Emergence of Nanotechnology to Fight HIV Sexual Transmission: The Trip of G2-S16 Polyanionic Carbosilane Dendrimer to Possible Pre-Clinical Trials.

Development of new, safe, and effective microbicides to prevent human immunodeficiency virus HIV sexual transmission is needed. Unfortunately, most microbicides proved ineffective to prevent the risk of HIV-infection in clinical trials. We are working with G2-S16 polyanionic carbosilane dendrimer (PCD) as a new possible vaginal topical microbicide, based on its short reaction times, wide availability, high reproducibility, and quantitative yields of reaction. G2-S16 PCD exerts anti-HIV activity at an early stage of viral replication, by blocking gp120/CD4/CCR5 interaction, and providing a barrier against infection for long periods of time. G2-S16 PCD was stable at different pH values, as well as in the presence of seminal fluids. It maintained the anti-HIV activity against R5/X4 HIV over time, did not generate any type of drug resistance, and retained the anti-HIV effect when exposed to semen-enhanced viral infection. Importantly, G2-S16 PCD did not modify vaginal microbiota neither in vitro or in vivo. Histopathological examination did not show vaginal irritation, inflammation, lesions, or damage in the vaginal mucosa, after administration of G2-S16 PCD at different concentrations and times in female mice and rabbit animal models. Based on these promising data, G2-S16 PCD could become a good, safe, and readily available candidate to use as a topical vaginal microbicide against HIV.

Nanoparticles in dermatologic surgery.

Nanotechnology is an emerging branch of science that involves the engineering of functional systems on the nanoscale (1-100 nm). Nanotechnology has been used in biomedical and therapeutic agents with the aim of providing novel treatment solutions where small molecule size may be beneficial for modulation of biologic function. Recent investigation in nanomedicine has become increasingly important to cutaneous pathophysiology, such as functional designs directed towards skin cancers and wound healing. This review outlines the application of nanoparticles relevant to dermatologic surgery.

Metal-based phosphorus dendrimers as novel nanotherapeutic strategies to tackle cancers: A concise overview.

Several metal-based phosphorus dendrimers were prepared. The first series developed by us was the Cu(II) series. In this series, the most potent is the third generation-Cu(II) showing original mechanism of action with activation of the pro-apoptotic Bax protein. To our knowledge, it is the first example of nanoparticles displaying Bax protein activation and then cell death through apoptosis process. Interestingly, this dendritic-Cu(II) complex showed synergistic effect with doxorubicin. Based on these interesting anti-proliferative activities, we developed Au(III)-conjugated phosphorus dendrimers. The most potent is the third generation-Au(III) dendrimer which represents also a new and promising first-in-class anti-proliferative agent against both solid and liquid tumor cell lines. Then, in order to analyze the influence of the metal moiety distribution of Cu(II) and Au(III) on the surface of dendrimers, mix Cu(II)-Au(III)-conjugated phosphorus dendrimers were also prepared and tested as anti-proliferative agents. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.

Phosphorus dendrimers for nanomedicine.

From biomaterials to imaging, and from drug delivery to drugs by themselves, phosphorus-containing dendrimers offer a large palette of biological properties, depending essentially on their types of terminal functions. The most salient examples of phosphorus dendrimers used for the elaboration of bio-chips and of supports for cell cultures, for imaging biological events, and for carrying and delivering drugs or biomacromolecules are presented in this feature article. Several phosphorus dendrimers can be considered also as drugs per se (by themselves) in particular to fight against cancers, neurodegenerative diseases, and inflammation, both in vitro and in vivo. Toxicity assays are also reported.

Nonnuclear Estrogen Receptor Activation Improves Hepatic Steatosis in Female Mice.

Estrogens have the potential to afford atheroprotection, to prevent excess adiposity and its metabolic complications including insulin resistance, and to lessen hepatic steatosis. Cellular responses to estrogens occur through gene regulation by nuclear estrogen receptors (ERs), and through signal initiation by plasma membrane-associated ER. Leveraging the potentially favorable cardiometabolic actions of estrogens has been challenging, because their reproductive tract and cancer-promoting effects adversely impact the risk to benefit ratio of the therapy. In previous works, we discovered that an estrogen dendrimer conjugate (EDC) comprised of ethinyl-estradiol (E2) molecules linked to a poly(amido)amine dendrimer selectively activates nonnuclear ER, and in mice, EDC does not invoke a uterotrophic response or support ER-positive breast cancer growth. In the present investigation, we employed EDC to determine how selective nonnuclear ER activation impacts atherosclerosis, adiposity, glucose homeostasis, and hepatic steatosis in female mice. In contrast to E2, EDC did not blunt atherosclerosis in hypercholesterolemic apoE-/- mice. Also in contrast to E2, EDC did not prevent the increase in adiposity caused by Western diet feeding in wild-type mice, and it did not affect Western diet-induced glucose intolerance. However, E2 and EDC had comparable favorable effect on diet-induced hepatic steatosis, and this was related to down-regulation of fatty acid and triglyceride synthesis genes in the liver. Predictably, only E2 caused a uterotrophic response. Thus, although nonnuclear ER activation does not prevent atherosclerosis or diet-induced obesity or glucose intolerance, it may provide a potential new strategy to combat hepatic steatosis without impacting the female reproductive tract or increasing cancer risk.

Tuning photothermal properties of gold nanodendrites for in vivo cancer therapy within a wide near infrared range by simply controlling their degree of branching.

Although dendritic nanoparticles have been prepared by many different methods, control over their degree of branching (DB) is still impossible, preventing us from understanding the effect of the DB on the properties of the nanodendrites as cancer therapeutics. Herein, we developed a novel seed-mediated method to prepare gold nanodendrites (AuNDs) in an organic solvent using long chain amines as a structural directing agent. We discovered that the DB could be tuned facilely by simply adjusting synthetic parameters, such as the solvent type, the type and concentration of the long chain amines. We found that DB tuning resulted in dramatic tunability in the optical properties in the near infrared (NIR) range, which led to significantly different performance in the photothermal cancer therapy. Our in vitro and in vivo studies revealed that AuNDs with a higher DB were more efficient in photothermal tumor destruction under a lower wavelength NIR irradiation. In contrast, those with a lower DB performed better in tumor destruction under a higher wavelength NIR irradiation, indicating that AuNDs of even lower DB should have even better photothermal cancer therapy efficiency within the second NIR window. Thus, the tunable optical properties of AuNDs in the NIR range allow us to selectively determine a suitable laser wavelength for the best cancer therapeutic performance.

HIV-antigens charged on phosphorus dendrimers as tools for tolerogenic dendritic cells-based immunotherapy.

AIMS: The objective was to study if cationic phosphorus dendrimers can be used as DC-based vaccine or adjuvant in anti-HIV-1 vaccine development when associated with HIV-1 derived peptides. MATERIALS & METHODS: The HIV derived peptides uptake in DC and the phenotype of iDC and mDC were studied using Flow Cytometry analysis. Migration of mDC was evaluated by an in vitro chemotaxis assay. Allogenic T-cells proliferative response induced by DC was studied using Flow Cytometry assays. Cytokines production was analysed by Diaclon DIAplex Th1/Th2/Inflammation kit. RESULTS: All phosphorus dendrimers showed the ability to deliver HIV-derived peptides in DC. The phosphorus dendrimers from second and third generations induced important changes in phenotype. Moreover, the treatment of mDC with the second generation dendrimer and derivated dendriplexes modified cellular migratory properties, altered their capacity to stimulate allogenic naïve T cells in vitro and impeded the production of pro-inflammatory cytokines. CONCLUSIONS: The phosphorus dendrimers cannot be used as vaccines because they would not have the ability to induce an immune response. The cationic phosphorus dendrimers associated with HIV-derived peptides have the ability to deliver peptides as non-viral vectors. However, there are other potential therapeutic applications of these compounds, for instance as topical antiinflammatory agents, as compounds for allograft rejection or autoimmune diseases and as agents inducing specific tolerance with antigen-loaded DC against allergy reaction. Nevertheless, these applications need to be evaluated.

Design of clinically useful macromolecular iron chelators.

OBJECTIVES: In recent years, macromolecular iron chelators have received increasing attention as human therapeutic agents. The objectives of this article are: one, to discuss the factors which should be considered when designing iron binding macromolecules as human therapeutic agents, and two, to report recent achievements in the design and synthesis of appropriate macromolecular chelators that have resulted in the production of a number of agents with therapeutic potential. KEY FINDINGS: Macromolecular drugs exhibit unique pharmaceutical properties that are fundamentally different from their traditional small-molecule counterparts. By virtue of their high-molecular-weight characteristics, many are confined to extracellular compartments, for instance, the serum and the gastrointestinal tract. In addition, they have potential for topical administration. Consequently, these macromolecular drugs are free from many of the toxic effects that are associated with their low-molecular-weight analogues. SUMMARY: The design and synthesis of macromolecular iron chelators provides a novel aspect to chelation therapy. 3-Hydroxypyridin-4-one hexadentate-based macromolecular chelators have considerable potential for the development of new treatments for iron overload and for topical treatment of infection.

Targeting cancer cells with DNA-assembled dendrimers: a mix and match strategy for cancer.

The unique biology of cancer requires the development of a multifunctional drug delivery system which can be efficiently manufactured to target subtle molecular alterations that distinguish a cancer cells from the many types of healthy cells found in the body. We sought to produce dendrimers conjugated to different bio-functional moieties [fluorescein (FITC) and folic acid (FA)], then link them together using complementary DNA oligonucleotides to produce clustered molecules that target cancer cells that over-express the high affinity folate receptor. This study demonstrates a unique molecular platform based on the DNA-directed assembly of dendritic polymers for the delivery of different agents to cancer cells. While only nanometers in diameter (the size of proteins), this DNA-linked dendrimer nanocluster platform is considered to allows for the delivery of drugs, genetic materials, and imaging agents to cancer cells, offering the potential for developing combinatorial therapeutics.