Superamphiphile Based Cross-Linked Small-Molecule Micelles for pH-Triggered Release of Anticancer Drugs

A new superamphiphile based cross-linked small-molecule micelle (SA-CSM) is developed for pH-triggered release of anticancer drugs. This strategy revolves around the use of a noncovalent superamphiphile formed by the elaborate zwitterion <b>1</b> and anticancer drug doxorubicin (DOX) via their “spontaneous attraction” of carboxylic acid and amino group. The superamphiphiles self-assemble into micelles in water, which were further stabilized by cross-linking the surface via the thiol-acrylate Michael addition to achieve the establishment of the pH-sensitive SA-CSMs. The biological evaluation shows that the new drug delivery system exhibits highly efficient anticancer efficacy both <i>in vitro</i>, on the HeLa cancer cell line, and <i>in vivo</i>, on the HeLa xenograft model, while suppressing the inherent toxicity of the employed chemotherapeutics. Compared with the reported covalent amphiphile based CSMs, the noncovalent superamphiphile based CSMs not only have comparable drug loading content (up to 45.0%), robust stability, and superior predictable biosafety but also feature nonchemical synthesis, low production cost, specific stimulus response, and anticancer activity of the original drugs and thus represent a good example for clinical application

Highly Efficient and Safe Delivery of VEGF siRNA by Bioreducible Fluorinated Peptide Dendrimers for Cancer Therapy

RNA interference (RNAi) has a great promise in treating various acquired and hereditary diseases. However, it remains highly desirable to develop new delivery system to circumvent complex extra- and intracellular barriers for successful clinical translation. Here, we report on a versatile polymeric vector, bioreducible fluorinated peptide dendrimers (BFPD), for efficient and safe small interfering RNA (siRNA) delivery. In virtue of skillfully integrating all of the unique advantages of reversible cross-linking, fluorination, and peptide dendrimers, this novel vector can surmount almost all extra- and intracellular barriers associated with local siRNA delivery through highly improved physiological stability and serum resistance, significantly increased intratumoral enrichment, cellular internalization, successful facilitation of endosomal escape, and cytosolic siRNA release. BFPD polyplexes, carrying small interfering vascular endothelial growth factor (siVEGF), demonstrated excellent VEGF silencing efficacy (∼65%) and a strong capability for inhibiting HeLa cell proliferation. More importantly, these polyplexes showed superior performance in long-term enrichment in the tumor sites and had a high level of tumor growth inhibition. Furthermore, these polyplexes not only exhibited excellent in vivo antitumor efficacy but also demonstrated superior biocompatibility, compared with LPF2000, both in vivo and in vitro. These findings indicate that BFPD is an efficient and safe siRNA delivery system and has remarkable potential for RNAi-based cancer treatment

Antibiotic-Loaded Chitosan Hydrogel with Superior Dual Functions: Antibacterial Efficacy and Osteoblastic Cell Responses

It is critical for the clinical success to take the biological function into consideration when integrating the antibacterial function into the implanted biomaterials. To this aim, we prepared gentamycin sulfate (GS)-loaded carboxymethyl-chitosan (CM-chitosan) hydrogel cross-linked by genipin. The prepared hydrogels not only achieved superb inhibition on bacteria growth and biofilm formation of <i>Staphylococcus aureus</i> but also significantly enhanced the adhesion, proliferation, and differentiation of MC3T3-E1 cells. The observed dual functions were likely based on the intrinsic property of the positive charged chitosan-based hydrogel, which could be modified to selectively disrupt the bacteria wall/membrane and promote cell adhesion and proliferation, as suggested by the membrane permeability study. The genipin concentration played an important role in controlling the degradation time of the chitosan hydrogel and the MC3T3-E1 cell responses. The loading of GS not only significantly increased the antibacterial efficiency but also was beneficial for the osteoblastic cell responses. Overall, the biocompatibility of the prepared chitosan-GS hydrogel could be tuned with both the genipin and GS concentrations, which control the available positive charged sites of chitosan. The results demonstrated that chitosan-GS hydrogel is an effective and simple approach to achieving combined antibacterial efficacy and excellent osteoblastic cell responses, which has great potential in orthopedic applications

Latent Naphthalimide Bearing Water-Soluble Nanoprobes with Catechol–Fe(III) Cores for in Vivo Fluorescence Imaging of Intracellular Thiols

Here, a novel latent naphthalimide bearing water-soluble nanoprobes with catechol–Fe­(III) cores (<b>Fe@LNNPs</b>) was designed, synthesized, and evaluated for in vivo fluorescence imaging of intracellular thiols, as various diseases are associated with overexpression of cellular biothiols. The <b>Fe@LNNPs</b> are mainly composed of three components. The inner part constitutes pyrocatechol groups, which can coordinate with Fe­(III) to form a cross-linked core for improving the stability in the complex biological environment. The naphthalimide group is linked by disulfide with the core to quench the probe fluorescence. The outer part is designed to be a hydrophilic glycol corona for prolonging blood circulation. Also, a biotin group can be easily introduced into the nanoprobe for actively targeting the HepG2 cells. The fluorescence spectra reveals that the <b>Fe@LNNPs</b> can be reduced explicitly by glutathione to trigger the fluorescence emission. Confocal microscopic imagings and animal experiments manifest that the <b>Fe@LNNPs</b>, especially with biotin groups, have much better fluorescence signal imaging compared to the reported small-molecule probe <b>1′</b> both in vitro and in vivo (up to 24 h). The <b>Fe@LNNPs</b> thus feature great advantages such as specificity, stability, biocompatibility, and long retention time for thiol-recognition imaging and hold potential applications in clinical cancer diagnosis

Bio-Inspired Supramolecular Hybrid Dendrimers Self-Assembled from Low-Generation Peptide Dendrons for Highly Efficient Gene Delivery and Biological Tracking

Currently, supramolecular self-assembly of dendrons and dendrimers emerges as a powerful and challenging strategy for developing sophisticated nanostructures with excellent performances. Here we report a supramolecular hybrid strategy to fabricate a bio-inspired dendritic system as a versatile delivery nanoplatform. With a rational design, dual-functionalized low-generation peptide dendrons (PDs) self-assemble onto inorganic nanoparticles <i>via</i> coordination interactions to generate multifunctional supramolecular hybrid dendrimers (SHDs). These SHDs exhibit well-defined nanostructure, arginine-rich peptide corona, and fluorescent signaling properties. As expected, our bio-inspired supramolecular hybrid strategy largely enhances the gene transfection efficiency of SHDs approximately 50 000-fold as compared to single PDs at the same R/P ratio. Meanwhile the bio-inspired SHDs also (i) provide low cytotoxicity and serum resistance in gene delivery; (ii) provide inherent fluorescence for tracking intracellular pathways including cellular uptake, endosomal escape, and gene release; and (iii) work as an alternative reference for monitoring desired protein expression. More importantly, <i>in vivo</i> animal experiments demonstrate that SHDs offer considerable gene transfection efficiency (in muscular tissue and in HepG2 tumor xenografts) and real-time bioimaging capabilities. These SHDs will likely stimulate studies on bio-inspired supramolecular hybrid dendritic systems for biomedical applications both <i>in vitro</i> and <i>in vivo</i>

Bioinspired Design of Stereospecific d‑Protein Nanomimics for High-Efficiency Autophagy Induction

Bioinspired Design of Stereospecific d‑Protein Nanomimics for High-Efficiency Autophagy Inductio

Cross-Linked Small-Molecule Micelle-Based Drug Delivery System: Concept, Synthesis, and Biological Evaluation

Lessons from the covalent capture of small-molecule self-assemblies (monomer molecular weight of <500.0) are applied to grow a generic cross-linked small-molecule micelle-based drug delivery system (CSM-DDS), which has significant advantages over the popular polymeric micelle-based drug delivery systems in terms of drug loading, stability, monomer purity, and cost of preparation. A proof-of-concept CSM-DDS constructed by one-step synthesized amphiphile <b>1</b> with anticancer drug gemcitabine confirms the feasibility of the new strategy via its high drug loading content (up to 58%), robust stability, superior predictable biosafety, facile functionalization, and remarkable anticancer activity both <i>in vitro</i> and <i>in vivo</i>

Bioreducible Peptide-Dendrimeric Nanogels with Abundant Expanded Voids for Efficient Drug Entrapment and Delivery

Dendrimer-based nanoplatforms have exhibited wide prospects in the field of nanomedicine for drug delivery, without great success due to many predicaments of cytotoxicity, high cost, and low yield. In this work, we report a feasible strategy on dynamic cross-linkings of low-generation peptide dendrimers into bioreducible nanogels for efficient drug controlled release. With a facile fabrication, the disulfide cross-linking of biocompatible peptide dendrimers successfully possess well-defined and stable nanostructures with abundant expanded voids for efficient molecular encapsulation. More importantly, high reducing condition is capable of triggering the cleavage of disulfide bonds, the disintegration of peptide-dendrimeric nanogels, and stimuli-responsive release of guest molecules. The bioreducible nanogels improve antitumor drug internalization, contribute to endosomal escape, and realize intracellular drug controlled release. The doxorubicin-loaded nanogels afford high antitumor efficiency and reduce the side effects to BALB/c mice bearing 4T1 tumor. Therefore, dynamic cross-linkings of low-generation dendrimers into smart nanogels will be an alternative and promising strategy to resolve the dilemmas of current dendrimer-based nanocarriers as well as develop innovative nanoplatforms

Tetraphenylethylene-Induced Cross-Linked Vesicles with Tunable Luminescence and Controllable Stability

Luminescence-tunable vesicles (LTVs) are becoming increasingly attractive for their potential application in optics, electronics, and biomedical technology. However, for real applications, luminous efficiency and durability are two urgent constraints to be overcome. Combining the advantages of aggregation-induced emission in luminous enhancement and cross-linking in stability, we herein fabricated tetraphenylethylene-induced cross-linked vesicles with an entrapped acceptor of RhB (TPE-CVs@RhB), which achieved a high-efficiency multicolor emission of the visible spectrum, including white, by altering the amount of entrapped acceptor. Stability tests show that the luminescence of TPE-CVs@RhB has excellent environmental tolerance toward heating, dilution, doping of organic solvent, and storage in serum. Further outstanding performance in the application of fluorescent inks suggests that the new LTVs hold high potential in industrialization. More attractively, although the TPE-CVs@RhB can tolerate various harsh conditions, their stability can actually be controlled through the cross-linker adopted. For example, the employment of dithiothreitol in the present work produces an acid-labile β-thiopropionate linker. The cellular uptake by HepG2 cells shows that the acid-labile TPE-CVs@RhB can effectively respond to the acidic environment of cancer cells and release the entrapped RhB molecules, indicative of promising applications of this new type of LTVs in bioimaging and drug delivery