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The need for chronic systemic immunosuppression, which is associated with unavoidable side-effects, greatly limits the applicability of allogeneic cell transplantation for regenerative medicine applications including pancreatic islet cell transplantation to restore insulin production in type 1 diabetes (T1D). Cell transplantation in confined sites enables the localized delivery of anti-inflammatory and immunomodulatory drugs to prevent graft loss by innate and adaptive immunity, providing an opportunity to achieve local effects while minimizing unwanted systemic side effects. Nanoparticles can provide the means to achieve the needed localized and sustained drug delivery either by graft targeting or co-implantation. Here, we evaluated the potential of our versatile platform of drug-integrating amphiphilic nanomaterial assemblies (DIANAs) for targeted drug delivery to an inflamed site model relevant for islet transplantation. We tested either passive targeting of intravenous administered spherical nanomicelles (nMIC; 20–25 nm diameter) or co-implantation of elongated nanofibrils (nFIB; 5 nm diameter and >1 μm length). To assess the ability of nMIC and nFIB to target an inflamed graft site, we used a lipophilic fluorescent cargo (DiD and DiR) and evaluated the in vivo biodistribution and cellular uptake in the graft site and other organs, including draining and non-draining lymph nodes, after systemic administration (nMIC) and/or graft co-transplantation (nFIB) in mice. Localized inflammation was generated either by using an LPS injection or by using biomaterial-coated islet-like bead implantation in the subcutaneous site. A cell transplant inflammation model was used as well to test nMIC- and nFIB-targeted biodistribution. We found that nMIC can reach the inflamed site after systemic administration, while nFIB remains localized for several days after co-implantation. We confirmed that DIANAs are taken up by different immune cell populations responsible for graft inflammation. Therefore, DIANA is a useful approach for targeted and/or localized delivery of immunomodulatory drugs to decrease innate and adaptive immune responses that cause graft loss after transplantation of therapeutic cells. [ABSTRACT FROM AUTHOR]

Octadecylazanediyl dipropionic acid (C18ADPA) is a zwitterionic amphiphile with a dendritic headgroup. C18ADPA self-assembles to lamellar networks, which encompasses water and forms a low-molecular-weight hydrogel (LMWG). In this study, we use the C18ADPA hydrogel as a drug carrier for the in vivo delivery of a copper salt for wound healing in a mouse model. A structural transition was observed based on cryo-scanning electron microscope (cryo-SEM) images after drug loading. The C18ADPA hydrogel, which had a layered structure, transformed into a self-assembled fibrillar network (SAFiN). The mechanical strength of the LMWG has always been an important issue in its applications. However, due to the structural transition, both the storage and loss moduli increased. In vivo tests showed that wound closure was faster after applying the hydrogel formulation compared with the Vaseline formulation. For the first time, we have also provided histological evidence of these effects on skin tissue. The hydrogel formulation exhibited clear advantages in regenerating tissue structure over traditional delivery formulations. [ABSTRACT FROM AUTHOR]

Peptides and their related compounds can self-assemble into diverse nanostructures of different shapes and sizes in response to various stimuli such as pH, temperature or ionic strength. Here we report the synthesis and characterization of a lysozyme derived pentapeptide and its ability to build well-defined fibrillar structures. Lysozyme FESNF peptide fragment was synthesized by solid phase peptide synthesis using the Fmoc/t-Bu strategy, purified by analytical high-performance liquid chromatography (HPLC) and its molecular weight was confirmed by matrix-assisted laser desorption/ionization mass spectrometry (MALDI–MS). Spectroscopic features of this pentapeptide were investigated by UV-visible spectroscopy and fluorimetry showing the pattern of marginal phenylalanine residues within the peptide sequence. Self-assembling properties were determined using atomic force microscopy (AFM), aggregation index and thioflavin T assay (ThT). FESNF generating fibrillar structures observed by AFM and aggregation propensity were primarily influenced by pH conditions. Moreover, the experimental data were confirmed by molecular dynamics simulation studies. The obtained fibrils will be used next to explore their potential to act as support material for medical and cosmetic application. [ABSTRACT FROM AUTHOR]

Protein-based materials intended as nanostructured drugs or drug carriers are progressively gaining interest in nanomedicine, since their structure, assembly and cellular interactivity can be tailored by recruiting functional domains. The main bottleneck in the development of deliverable protein materials is the lysosomal degradation that follows endosome maturation. This is especially disappointing in the case of receptor-targeted protein constructs, which, while being highly promising and in demand in precision medicines, enter cells via endosomal/lysosomal routes. In the search for suitable protein agents that might promote endosome escape, we have explored the translocation domain (TD) of the diphtheria toxin as a functional domain in CXCR4-targeted oligomeric nanoparticles designed for cancer therapies. The pharmacological interest of such protein materials could be largely enhanced by improving their proteolytic stability. The incorporation of TD into the building blocks enhances the amount of the material detected inside of exposed CXCR4+ cells up to around 25-fold, in absence of cytotoxicity. This rise cannot be accounted for by endosomal escape, since the lysosomal degradation of the new construct decreases only moderately. On the other hand, a significant loss in the specificity of the CXCR4-dependent cellular penetration indicates the unexpected role of the toxin segment as a cell-penetrating peptide in a dose-dependent and receptor-independent fashion. These data reveal that the diphtheria toxin TD displayed on receptor-targeted oligomeric nanoparticles partially abolishes the exquisite receptor specificity of the parental material and it induces nonspecific internalization in mammalian cells. [ABSTRACT FROM AUTHOR]

Tissue regeneration is a prominent area of research, developing biomaterials aimed to be tunable, mechanistic scaffolds that mimic the physiological environment of the tissue. These biomaterials are projected to effectively possess similar chemical and biological properties, while at the same time are required to be safely and quickly degradable in the body once the desired restoration is achieved. Supramolecular systems composed of reversible, non-covalently connected, self-assembly units that respond to biological stimuli and signal cells have efficiently been developed as preferred biomaterials. Their biocompatibility and the ability to engineer the functionality have led to promising results in regenerative therapy. This review was intended to illuminate those who wish to envisage the niche translational research in regenerative therapy by summarizing the various explored types, chemistry, mechanisms, stimuli receptivity, and other advancements of supramolecular systems. [ABSTRACT FROM AUTHOR]

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

In part I of this review, the authors showed how poly(amidoamine) (PAMAM)-based dendrimers can be considered as promising delivering platforms for siRNA therapeutics. This is by virtue of their precise and unique multivalent molecular architecture, characterized by uniform branching units and a plethora of surface groups amenable to effective siRNA binding and delivery to e.g., cancer cells. However, the successful clinical translation of dendrimer-based nanovectors requires considerable amounts of good manufacturing practice (GMP) compounds in order to conform to the guidelines recommended by the relevant authorizing agencies. Large-scale GMP-standard high-generation dendrimer production is technically very challenging. Therefore, in this second part of the review, the authors present the development of PAMAM-based amphiphilic dendrons, that are able to auto-organize themselves into nanosized micelles which ultimately outperform their covalent dendrimer counterparts in in vitro and in vivo gene silencing.

Peptide drugs hold great promise for the treatment of infectious diseases thanks to their novel mechanisms of action, low toxicity, high specificity, and ease of synthesis and modification. Naturally developing self-assembly in nature has inspired remarkable interest in self-assembly of peptides to functional nanomaterials. As a matter of fact, their structural, mechanical, and functional advantages, plus their high bio-compatibility and bio-degradability make them excellent candidates for facilitating biomedical applications. This review focuses on the self-assembly of peptides for the fabrication of antibacterial nanomaterials holding great interest for substituting antibiotics, with emphasis on strategies to achieve nano-architectures of self-assembly. The antibacterial activities achieved by these nanomaterials are also described.

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

In part I of this review, the authors showed how poly(amidoamine) (PAMAM)-based dendrimers can be considered as promising delivering platforms for siRNA therapeutics. This is by virtue of their precise and unique multivalent molecular architecture, characterized by uniform branching units and a plethora of surface groups amenable to effective siRNA binding and delivery to e.g., cancer cells. However, the successful clinical translation of dendrimer-based nanovectors requires considerable amounts of good manufacturing practice (GMP) compounds in order to conform to the guidelines recommended by the relevant authorizing agencies. Large-scale GMP-standard high-generation dendrimer production is technically very challenging. Therefore, in this second part of the review, the authors present the development of PAMAM-based amphiphilic dendrons, that are able to auto-organize themselves into nanosized micelles which ultimately outperform their covalent dendrimer counterparts in in vitro and in vivo gene silencing. [ABSTRACT FROM AUTHOR]

Peptide drugs hold great promise for the treatment of infectious diseases thanks to their novel mechanisms of action, low toxicity, high specificity, and ease of synthesis and modification. Naturally developing self-assembly in nature has inspired remarkable interest in self-assembly of peptides to functional nanomaterials. As a matter of fact, their structural, mechanical, and functional advantages, plus their high bio-compatibility and bio-degradability make them excellent candidates for facilitating biomedical applications. This review focuses on the self-assembly of peptides for the fabrication of antibacterial nanomaterials holding great interest for substituting antibiotics, with emphasis on strategies to achieve nano-architectures of self-assembly. The antibacterial activities achieved by these nanomaterials are also described. [ABSTRACT FROM AUTHOR]