Biological Response Following the Systemic Injection of PEG-PAMAM-Rhodamine Conjugates in Zebrafish.

Numerous therapeutic and diagnostic approaches used within a clinical setting depend on the administration of compounds via systemic delivery. Biomaterials at the nanometer scale, as dendrimers, act as delivery systems by improving cargo bioavailability, circulation time, and the targeting of specific tissues. Although evaluating the efficacy of pharmacological agents based on nanobiomaterials is crucial, conducting toxicological assessments of biomaterials is essential for advancing clinical translation.

Dendrimers and Derivatives as Multifunctional Nanotherapeutics for Alzheimer's Disease.

Alzheimer's disease (AD) is the most prevalent form of dementia. It affects more than 30 million people worldwide and costs over US$ 1.3 trillion annually.

Enhancement of hMSC In Vitro Proliferation by Surface Immobilization of a Heparin-Binding Peptide.

The use of human Mesenchymal Stem Cells (hMSC) as therapeutic agents for advanced clinical therapies relies on their in vitro expansion. Over the last years, several efforts have been made to optimize hMSC culture protocols, namely by mimicking the cell physiological microenvironment, which strongly relies on signals provided by the extracellular matrix (ECM). ECM glycosaminoglycans, such as heparan-sulfate, sequester adhesive proteins and soluble growth factors at the cell membrane, orchestrating signaling pathways that control cell proliferation.

Unravelling the interactions of biodegradable dendritic nucleic acid carriers and neural cells.

Nanomedicines based on nanoparticles as carriers of therapeutics are expected to drastically influence the future of healthcare. However, clinical translation of these technologies can be very challenging. The development process of nanoparticles for biological applications encompasses the analysis and understanding of several steps , before , and subsequent clinical applications, namely, the in-depth study of biosafety, cellular interaction, and intracellular trafficking.

Antimicrobial peptide-grafted PLGA-PEG nanoparticles to fight bacterial wound infections.

Wound infection treatment with antimicrobial peptides (AMPs) is still not a reality, due to the loss of activity . Unlike the conventional strategy of encapsulating AMPs on nanoparticles (NPs) leaving activity dependent on the release profile, this work explores AMP grafting to poly(D,L-lactide--glycolide)-polyethylene glycol NPs (PLGA-PEG NPs), whereby AMP exposition, infection targeting and immediate action are promoted. NPs are functionalized with MSI-78(4-20), an equipotent and more selective derivative of MSI-78, grafted through a thiol-maleimide (Mal) Michael addition.

Versatile fully biodegradable dendritic nanotherapeutics.

The repeated administration of non-degradable dendrimers can lead to toxicity due to their bioaccumulation. Furthermore, in drug delivery applications, carrier stability can result in low biological performance due to insufficient intracellular cargo release. A novel family of versatile, biosafe, water-soluble, and fully biodegradable PEG-dendritic nanosystems is proposed, which overcomes the limitations of the most used dendrimers.

Grafting MSI-78A onto chitosan microspheres enhances its antimicrobial activity.

MSI-78A (Pexiganan A) is one of the few antimicrobial peptides (AMPs) able to kill Helicobacter pylori, a pathogenic bacterium that colonizes the gastric mucosa of half of the world's population. Antibiotics fail in 20-40% of H. pylori-infected patients, reinforcing the need for alternative treatments.

Breaking Barriers: Bioinspired Strategies for Targeted Neuronal Delivery to the Central Nervous System.

Central nervous system (CNS) disorders encompass a vast spectrum of pathological conditions and represent a growing concern worldwide. Despite the high social and clinical interest in trying to solve these pathologies, there are many challenges to bridge in order to achieve an effective therapy. One of the main obstacles to advancements in this field that has hampered many of the therapeutic strategies proposed to date is the presence of the CNS barriers that restrict the access to the brain.

PAMAM dendrimers: blood-brain barrier transport and neuronal uptake after focal brain ischemia.

Drug delivery to the central nervous system is restricted by the blood-brain barrier (BBB). However, with the onset of stroke, the BBB becomes leaky, providing a window of opportunity to passively target the brain. Here, cationic poly(amido amine) (PAMAM) dendrimers of different generations were functionalized with poly(ethylene glycol) (PEG) to reduce cytotoxicity and prolong blood circulation half-life, aiming for a safe in vivo drug delivery system in a stroke scenario.

Fine tuning neuronal targeting of nanoparticles by adjusting the ligand grafting density and combining PEG spacers of different length.

Unlabelled: Poly(ethylene glycol) (PEG) has been extensively used to coat the surface of nanocarriers to improve their physicochemical properties and allow the grafting of targeting moieties. Still, to date there is no common agreement on the ideal PEG coverage-density or length to be used for optimum vector performance. In this study, we aimed to investigate the impact of both PEG density and length on the vectoring capacity of neuron-targeted gene-carrying trimethyl chitosan nanoparticles.

Biodegradable PEG-dendritic block copolymers: synthesis and biofunctionality assessment as vectors of siRNA.

One important drawback of most of the currently used dendrimers for biomedical applications is their high stability under physiological conditions that can result in cytotoxicity or complications induced by the accumulation of non-degradable synthetic materials in the organism. Particularly in the gene therapy field, vector stability can further hinder the intracellular release of the nucleic acid from the dendriplex, consequently leading to low transfection efficiencies. Therefore, biodegradable cationic dendritic structures have been eagerly awaited.

Delivering siRNA with Dendrimers: In Vivo Applications.

Over the last decades, gene therapy has emerged as a pioneering therapeutic approach to treat or prevent several diseases. Among the explored strategies, the short-term silencing of protein coding genes mediated by siRNAs has a good therapeutic potential in a clinical setting. However, the widespread use of siRNA will require the development of clinically suitable, safe and effective vehicles with the ability to complex and deliver siRNA into target cells with minimal toxicity.

A high-throughput bioimaging study to assess the impact of chitosan-based nanoparticle degradation on DNA delivery performance.

Unlabelled: By using imaging flow cytometry as a powerful statistical high-throughput technique we investigated the impact of degradation on the biological performance of trimethyl chitosan (TMC)-based nanoparticles (NPs). In order to achieve high transfection efficiencies, a precise balance between NP stability and degradation must occur. We altered the biodegradation rate of the TMC NPs by varying the degree of acetylation (DA) of the polymer (DA ranged from 4 to 21%), giving rise to NPs with different enzymatic degradation profiles.

Delivery of Splice Switching Oligonucleotides by Amphiphilic Chitosan-Based Nanoparticles.

Splice switching oligonucleotides (SSOs) are a class of single-stranded antisense oligonucleotides (ssONs) being used as gene therapeutics and demonstrating great therapeutic potential. The availability of biodegradable and biocompatible delivery vectors that could improve delivery efficiencies, reduce dosage, and, in parallel, reduce toxicity concerns could be advantageous for clinical translation. In this work we explored the use of quaternized amphiphilic chitosan-based vectors in nanocomplex formation and delivery of splice switching oligonucleotides (SSO) into cells, while providing insights regarding cellular uptake of such complexes.

Functionalized chitosan derivatives as nonviral vectors: physicochemical properties of acylated N,N,N-trimethyl chitosan/oligonucleotide nanopolyplexes.

Cationic polymers have recently attracted attention due to their proven potential for nonviral gene delivery. In this study, we report novel biocompatible nanocomplexes produced using chemically functionalized N,N,N-trimethyl chitosan (TMC) with different N-acyl chain lengths (C5-C18) associated with single-stranded oligonucleotides. The TMC derivatives were synthesized by covalent coupling reactions of quaternized chitosan with n-pentanoic (C5), n-decanoic (C10), and n-octadecanoic (C18) fatty acids, which were extensively characterized by Fourier transform-infrared spectroscopy (FT-IR) and proton nuclear magnetic resonance ((1)H NMR).

The Present and the Future of Degradable Dendrimers and Derivatives in Theranostics.

Interest in dendrimer-based nanomedicines has been growing recently, as it is possible to precisely manipulate the molecular weight, chemical composition, and surface functionality of dendrimers, tuning their properties according to the desired biomedical application. However, one important concern about dendrimer-based therapeutics remains-the nondegradability under physiological conditions of the most commonly used dendrimers. Therefore, biodegradable dendrimers represent an attractive class of nanomaterials, since they present advantages over conventional nondegradable dendrimers regarding the release of the loaded molecules and the prevention of bioaccumulation of synthetic materials and subsequent cytotoxicity.

Using a combination of magnetic anisotropic effects for the configurational assignment of amino alcohols.

The combined magnetic anisotropic effects generated by two auxiliary moieties of 2-methoxy-2-phenylacetic acid (MPA), introduced on two families of terminal 1,2-amino alcohols (prim/sec and sec/prim), determine the signs of the Deltadelta(RS) parameters-the differences in chemical shifts between the bis-(R)-MPA and the bis-(S)-MPA esters-of the hydrogen atoms placed at both sides of the stereogenic carbon atoms, thereby allowing the determination of the absolute configuration of those heterobifunctional compounds. Theoretical (AM1, B3LYP) and experimental (CD, (3)J, low-temperature NMR spectroscopy, isotopic labeling) studies, together with testing with a number of representative compounds, permit one to establish the foundations of this methodology.

Assigning the configuration of amino alcohols by NMR: a single derivatization method.

The chirality of sec/prim- and prim/sec-1,2-amino alcohols can be determined by (1)H NMR of just one MPA derivative--either (R) or (S)--by comparison of two spectra at different temperatures and analysis of the evolution of the easily observable singles of the CalphaH signals.

Cross interaction between auxiliaries: the chirality of amino alcohols by NMR.

The absolute configuration of sec/prim- and prim/sec-1,2-amino alcohols is determined by comparison of the (1)H NMR chemical shifts of the auxiliary OMe or CalphaH groups at the corresponding bis-( R) and bis-( S)-MPA derivatives. This is the first NMR method that allows the assignment of absolute configuration without resorting to the shifts of hydrogens at the substrate and is based on the cross anisotropic interactions between auxiliaries.

Absolute configuration of amino alcohols by 1H-NMR.

A general NMR spectroscopy protocol for determination of absolute configuration of 1,2-amino alcohols, that allows differentiation of the four possible stereoisomers by analysis of the 1H NMR spectra of their bis-MPA derivatives, is described.