New modular platform based on multi-adjuvanted amphiphilic chitosan nanoparticles for efficient lipopeptide vaccine delivery against group A streptococcus.
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ABSTRACT:
SUBMITTER: Norpi ASM
PROVIDER: S-EPMC9237632 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Amphiphilic copolymers with pendant functional groups in polyester segments are widely used in nanomedicine. These enriched functionalities are designed to form covalent conjugates with payloads or provide additional stabilization effects for encapsulated drugs. A general method is successfully developed for the efficient preparation of functional biodegradable PEG-polyester copolymers via click chemistry. Firstly, in the presence of mPEG as initiator, Sn(Oct)2-catalyzed ring-opening polymerization of the α-alkynyl functionalized lactone with D,L-lactide or ε-caprolactone afforded linear mPEG-polyesters bearing multiple pendant alkynyl groups. Kinetic studies indicated the formation of random copolymers. Through copper-catalyzed azide-alkyne cycloaddition reaction, various small azido molecules with different functionalities to polyester segments are efficiently grafted. The molecular weights, polydispersities and grafting efficiencies of azido molecules of these copolymers were investigated by NMR and GPC. Secondly, it is demonstrated that the resulting amphiphilic functional copolymers with low CMC values could self-assemble to form nanoparticles in aqueous media. In addition, the in vitro degradation study and cytotoxicity assays indicated the excellent biodegradability and low cytotoxicity of these copolymers. This work provides a general approach toward the preparation of functional PEG-polyester copolymers in a quite efficient way, which may further facilitate the application of functional PEG-polyesters as drug delivery materials.
| S-EPMC8508947 | biostudies-literature
Project description:A number of amphiphilic cyclic peptides-[FR]4, [WR]5, and [WK]5-containing hydrophobic and positively-charged amino acids were synthesized by Fmoc/tBu solid-phase peptide methods and evaluated for their efficiency in intracellular delivery of siRNA to triple-negative breast cancer cell lines, MDA-MB-231 and MDA-MB-468, in the presence and absence of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE). Among the peptides, [WR]5, which contains alternate tryptophan (W) and arginine (R) residues, was found to be the most efficient in the delivery of siRNA by improving the delivery by more than 3-fold when compared to other synthesized cyclic peptides that were not efficient. The data also showed that co-formulation of [WR]5 with lipid DOPE significantly enhanced the efficiency of siRNA delivery by up to ~2-fold compared to peptide alone. Based on the data indicating the efficiency of [WR]5 in siRNA delivery, peptides containing arginine residues on the ring and tryptophan residues on the side chain, [R6K]W6 and [R5K]W5, were also evaluated, and demonstrated improved delivery of siRNA. The presence of DOPE again enhanced the siRNA delivery in most cases. [WR]5, [R5K]W5, and [R6K]W6 did not show any significant toxicity in MDA-MB-231, MDA-MB-468, and AU565 WT cells at N/P ratios of 20:1 or less, in the presence and absence of DOPE. Silencing of kinesin spindle protein (KSP) and Janus kinase 2 (JAK2) was evaluated in MDA-MB-231 cells in the presence of the peptides. The addition of DOPE significantly enhanced the silencing efficiency for all selected peptides. In conclusion, peptides containing tryptophan and arginine residues were found to enhance siRNA delivery and to generate silencing of targeted proteins in the presence of DOPE.
| S-EPMC6523661 | biostudies-literature
Project description:The upper respiratory tract (URT) is the major entry site for human pathogens and strategies to activate this network could lead to new vaccines capable of preventing infection with many pathogens. Group A streptococcus (GAS) infections, causing rheumatic fever, rheumatic heart disease, and invasive disease, are responsible for substantial morbidity and mortality. We describe an innovative vaccine strategy to induce mucosal antibodies of significant magnitude against peptide antigens of GAS using a novel biocompatible liposomal platform technology. The approach is to encapsulate free diphtheria toxoid (DT), a standard vaccine antigen, within liposomes as a source of helper T-cell stimulation while lipidated peptide targets for B-cells are separately displayed on the liposome surface. As DT is not physically conjugated to the peptide, it is possible to develop modular epitopic constructs that simultaneously activate IgA-producing B-cells of different and complementary specificity and function that together neutralize distinct virulence factors. An inflammatory cellular immune response is also induced. The immune response provides profound protection against streptococcal infection in the URT. The study describes a new vaccine platform for humoral and cellular immunity applicable to the development of vaccines against multiple mucosal pathogens.
| S-EPMC5157026 | biostudies-literature
Project description:Modularly clickable polymer-caged nanobins (PCNs) were prepared from liposome templates using a drop-in cholesterol-modified poly(acrylic acid) reagent followed by cross-linking with alkyne-functionalized diamine linker that allows for the conjugation of azide-modified targeting ligands via click ligation. These PCNs possess pH-responsive characteristics that can be used to trigger the release of encapsulated doxorubicin (DXR) payload inside the liposomal core under mild acidic conditions. After click-conjugation with azide-modified folate as an active targeting ligand, the resulting folate-conjugated, DXR-loaded PCNs (f-PCN(DXR)) demonstrated enhanced potency to folate receptor (FR)-positive tumor cells such as KB and OvCa432 over FR-negative MCF7 cells. f-PCN(DXR) can readily discriminate FR-positive tumor cells as a function of the level of cellular FR-expression, showing different degrees of potentiation in each cell. With both targeting functionalities and pH-sensitive drug-releasing triggers, f-PCN(DXR) was fifty-times more potent than the untargeted agent toward cancer cells that overexpress the folate target receptors.
| S-EPMC3650134 | biostudies-literature
Project description:Self-assembled peptide nanostructures recently have gained much attention as drug delivery systems. As biomolecules, peptides have enhanced biocompatibility and biodegradability compared to polymer-based carriers. We introduce a peptide nanoparticle system containing arginine, histidine, and an enzyme-responsive core of repeating GLFG oligopeptides. GLFG oligopeptides exhibit specific sensitivity towards the enzyme cathepsin B that helps effective controlled release of cargo molecules in the cytoplasm. Arginine can induce cell penetration, and histidine facilitates lysosomal escape by its buffering capacity. Herein, we propose an enzyme-responsive amphiphilic peptide delivery system (Arg-His-(Gly-Phe-Lue-Gly)3, RH-(GFLG)3). The self-assembled RH-(GFLG)3 globular nanoparticle structure exhibited a positive charge and formulation stability for 35 days. Nile Red-tagged RH-(GFLG)3 nanoparticles showed good cellular uptake compared to the non-enzyme-responsive control groups with d-form peptides (LD (LRH-D(GFLG)3), DL (DRH-L(GFLG)3), and DD (DRH-D(GFLG)3). The RH-(GFLG)3 nanoparticles showed negligible cytotoxicity in HeLa cells and human RBCs. To determine the drug delivery efficacy, we introduced the anticancer drug doxorubicin (Dox) in the RH-(GFLG)3 nanoparticle system. LL-Dox exhibited formulation stability, maintaining the physical properties of the nanostructure, as well as a robust anticancer effect in HeLa cells compared to DD-Dox. These results indicate that the enzyme-sensitive RH-(GFLG)3 peptide nanoparticles are promising candidates as drug delivery carriers for biomedical applications.
| S-EPMC8779831 | biostudies-literature
Project description:A modular p-phosphonated calix[4]arene vesicle (PCV) loaded with paclitaxel (PTX) and conjugated with folic acid as a cancer targeting ligand has been prepared using a thin film-sonication method. It has a pH-responsive capacity to trigger the release of the encapsulated PTX payload under mildly acidic conditions. PTX-loaded PCV conjugated with alkyne-modified PEG-folic acid ligands prepared via click ligation (fP-PCVPTX) has enhanced potency against folate receptor (FR)-positive SKOV-3 ovarian tumour cells over FR-negative A549 lung tumour cells. Moreover, fP-PCVPTX is also four times more potent than the non-targeting PCVPTX platform towards SKOV-3 cells. Overall, as a delivery platform the PCVs have the potential to enhance efficacy of anticancer drugs by targeting a chemotherapeutic payload specifically to tumours and triggering the release of the encapsulated drug in the vicinity of cancer cells.
| S-EPMC4806332 | biostudies-literature
Project description:Since the recent clinical approval of siRNA-based drugs and COVID-19 mRNA vaccines, the potential of RNA therapeutics for patient healthcare has become widely accepted. Lipid nanoparticles (LNPs) are currently the most advanced nanocarriers for RNA packaging and delivery. Nevertheless, the intracellular delivery efficiency of state-of-the-art LNPs remains relatively low and safety and immunogenicity concerns with synthetic lipid components persist, altogether rationalizing the exploration of alternative LNP compositions. In addition, there is an interest in exploiting LNP technology for simultaneous encapsulation of small molecule drugs and RNA in a single nanocarrier. Here, we describe how well-known tricyclic cationic amphiphilic drugs (CADs) can be repurposed as both structural and functional components of lipid-based NPs for mRNA formulation, further referred to as CADosomes. We demonstrate that selected CADs, such as tricyclic antidepressants and antihistamines, self-assemble with the widely-used helper lipid DOPE to form cationic lipid vesicles for subsequent mRNA complexation and delivery, without the need for prior lipophilic derivatization. Selected CADosomes enabled efficient mRNA delivery in various in vitro cell models, including easy-to-transfect cancer cells (e.g. human cervical carcinoma HeLa cell line) as well as hard-to-transfect primary cells (e.g. primary bovine corneal epithelial cells), outperforming commercially available cationic liposomes and state-of-the-art LNPs. In addition, using the antidepressant nortriptyline as a model compound, we show that CADs can maintain their pharmacological activity upon CADosome incorporation. Furthermore, in vivo proof-of-concept was obtained, demonstrating CADosome-mediated mRNA delivery in the corneal epithelial cells of rabbit eyes, which could pave the way for future applications in ophthalmology. Based on our results, the co-formulation of CADs, helper lipids and mRNA into lipid-based nanocarriers is proposed as a versatile and straightforward approach for the rational development of drug combination therapies.
| S-EPMC9401634 | biostudies-literature
Project description:Limited drug loading capacity (LC), mostly below 5% w/w, is a significant drawback of nanoparticulate drug delivery systems (DDS). Squalenoylation technology, which employs bioconjugation of squalenyl moiety and drug, allows self-assemble of nanoparticles (NPs) in aqueous media with significantly high LC (>30% w/w). The synthesis and particle preparation of squalenoylated prodrugs are, however, not facile for molecules with multiple reactive groups. Taking a different approach, we describe the synthesis of amphiphilic squalenyl derivatives (SqDs) as well as the physicochemical and biopharmaceutical characterizations of their self-assembled NPs as DDSs. The SqDs included in this study are (i) cationic squalenyl diethanolamine (ii) PEGylated SqD (PEG 750 Da), (iii) PEGylated SqD (PEG 3,000 Da), and (iv) anionic squalenyl hydrogen sulfate. All four SqDs self-assemble into NPs in a size range from 100 to 200 nm in an aqueous solution. Furthermore, all NP derivatives demonstrate appropriate biocompatibility and adequate colloidal stability in physiological relevant pH environments. The mucoprotein binding of PEGylated NPs is reduced compared to the charged NPs. Most importantly, this technology allows excellent LC (at maximum of 45% w/w) of a wide range of multifunctional compounds, varying in physicochemical properties and molecular weight. Interestingly, the drug release profile can be tuned by different loading methods. In summary, the SqD-based NPs appear as versatile drug delivery platforms.
| S-EPMC7604382 | biostudies-literature
Project description:Helicobacter pylori (H. pylori) colonize the stomach epithelium of half the world's population and are responsible for a variety of digestive diseases and even stomach cancer. The protection against H. pylori infection depends primarily on the antigen-mediated mucosal and T cell responses. We hypothesized that lipopeptide vaccines obtained by covalently conjugation of Pam2Cys with strong mucosal adjuvant activity to the immunodominant epitope from protective antigens could induce protective responses against H. pylori infection. In this study, the synthetic lipopeptide vaccines, Hp4 (Pam2Cys modified UreB T cell epitope) and Hp10 (Pam2Cys modified CagA T/B cell combined epitope), induced the BMDCs maturation in vitro by activating a variety of pattern recognition receptors such as TLR, NLR and RLR. In addition, lipopeptide vaccines stimulated BMDCs to secret cytokines that have the potential to modulate T cell activation and differentiation. Although intranasal immunization with Hp4 or Hp10 elicited robust epitope-specific T cell responses in mice, only Hp10 conferred protection against H. pylori infection, possibly due to the fact that Hp10 also induced substantial specific sIgA response at mucosal sites. Interestingly, when two lipopeptide vaccines were administrated in combination, Hp4 elevated the protective response against H. pylori infection of Hp10, which was characterized by better protective effect and enhanced specific T cell and mucosal antibody responses. Our results suggest that synthetic lipopeptide vaccines based on the epitopes derived from the protective antigens are promising candidates for protection against H. pylori infection.
2023-01-01 | GSE218459 | GEO
Project description:BackgroundModular nanotransporters (MNT) are recombinant multifunctional polypeptides created to exploit a cascade of cellular processes, initiated with membrane receptor recognition to deliver selective short-range and highly cytotoxic therapeutics to the cell nucleus. This research was designed for in vivo concept testing for this drug delivery platform using two modular nanotransporters, one targeted to the ?-melanocyte-stimulating hormone (?MSH) receptor overexpressed on melanoma cells and the other to the epidermal growth factor (EGF) receptor overexpressed on several cancers, including glioblastoma, and head-and-neck and breast carcinoma cells.MethodsIn vivo targeting of the modular nanotransporter was determined by immuno-fluorescence confocal laser scanning microscopy and by accumulation of (125)I-labeled modular nanotransporters. The in vivo therapeutic effects of the modular nanotransporters were assessed by photodynamic therapy studies, given that the cytotoxicity of photosensitizers is critically dependent on their delivery to the cell nucleus.ResultsImmunohistochemical analyses of tumor and neighboring normal tissues of mice injected with multifunctional nanotransporters demonstrated preferential uptake in tumor tissue, particularly in cell nuclei. With (125)I-labeled MNT{?MSH}, optimal tumor:muscle and tumor:skin ratios of 8:1 and 9.8:1, respectively, were observed 3 hours after injection in B16-F1 melanoma-bearing mice. Treatment with bacteriochlorin p-MNT{?MSH} yielded 89%-98% tumor growth inhibition and a two-fold increase in survival for mice with B16-F1 and Cloudman S91 melanomas. Likewise, treatment of A431 human epidermoid carcinoma-bearing mice with chlorin e(6)- MNT{EGF} resulted in 94% tumor growth inhibition compared with free chlorin e(6), with 75% of animals surviving at 3 months compared with 0% and 20% for untreated and free chlorin e(6)-treated groups, respectively.ConclusionThe multifunctional nanotransporter approach provides a new in vivo functional platform for drug development that could, in principle, be applicable to any combination of cell surface receptor and agent (photosensitizers, oligonucleotides, radionuclides) requiring nuclear delivery to achieve maximum effectiveness.
| S-EPMC3277434 | biostudies-literature