Small interfering RNA (siRNA) is emerging as novel therapeutics for treating various diseases, provided a safe and efficient delivery is available. In particular, specific delivery to target cells is critical for achieving high therapeutic efficacy while reducing toxicity. Amphiphilic dendrimers are emerging as novel promising carriers for siRNA delivery by virtue of the combined multivalent cooperativity of dendrimers with the self-assembling property of lipid vectors. Here, we report a ballistic approach for targeted siRNA delivery to cancer cells using an amphiphilic dendrimer equipped with dual targeting peptide bearing RGDK warhead. According to the molecular design, the amphiphilic dendrimer was expected to perform effective siRNA delivery while the targeting peptide was to home in on tumors via interaction of its warhead with integrin and the neuropilin-1 receptor on cancer cells. Coating the positively charged siRNA/dendrimer delivery complex with the negatively charged segment of the targeting peptide via electrostatic interactions led to small and stable nanoparticles able to protect siRNA from degradation, maintain accessibility of RGDK for targeting cancer cells, and preserve endosome escape capacity. The targeted system had enhanced siRNA delivery, stronger gene silencing and more potent anticancer activity compared to non-targeted or covalent dendrimer-based systems. In addition, neither acute toxicity nor induced inflammation was observed. Consequently, this delivery system constitutes a promising nonviral vector for targeted delivery and can be further applied for elaborating RNAi-based personalized medicine against cancer. Our study also demonstrates that nanotechnology based on self-assembling dendrimers can contribute new perspectives in various biomedical applications.

Three novel indolosesquiterpenes, xiamycin B (1b), indosespene (2), and sespenine (3), along with the known xiamycin A (1a) were isolated from the culture broth of Streptomyces sp. HKI0595, a bacterial endophyte of the widespread mangrove tree Kandelia candel. Agar diffusion assays revealed moderate to strong antimicrobial activities against several bacteria, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis, while no cytotoxicity against human tumor cell lines was observed. Together with the previously reported oridamycin, the endophyte metabolites represent the first indolosesquiterpenes isolated from prokaryotes.

Dendrimers, notable for their well-defined radial structures with numerous terminal functionalities, hold great promise for biomedical applications such as drug delivery, diagnostics, and therapeutics. However, their translation into clinical use has been greatly impeded by their challenging stepwise synthesis and difficult purification. To circumvent these obstacles, we have pioneered a self-assembly approach to constructing noncovalent supramolecular dendrimers using small amphiphilic dendrimer building units which can be easily synthesized and purified. By virtue of their amphipathic nature, the small amphiphilic dendrimers are able to self-assemble and generate large supramolecular dendrimers via noncovalent weak interactions such as van der Waals forces, H bonds, and electrostatic interactions. The so-created noncovalent dendrimers can mimic covalent dendrimers not only in terms of the radial structural feature emanating from a central core but also in their capacity to deliver drugs and imaging agents for biomedical applications. The noncovalent supramolecular dendrimers can be easily synthesized and modulated with regard to size, shape, and properties by varying the nature of the hydrophobic and hydrophilic entities as well as the dendrimer generation and terminal functionalities, ensuring their adaptability to specific applications. In particular, the dendritic structure of the amphiphilic building units permits the creation of large void spaces within the formed supramolecular dendrimers for the physical encapsulation of drugs, while the large number of surface functionalities can be exploited for both physical and chemical conjugation of pharmaceutic agents for drug delivery. Poly(amidoamine) (PAMAM) dendrimers are the most intensively studied for biomedical applications by virtue of their excellent biocompatibility imparted by their peptide-mimicking amide backbones and numerous interior and terminal amine functionalities. We present a short overview of our self-assembly strategy for constructing supramolecular PAMAM dendrimers for biomedical applications. Specifically, we start with the introduction of dendrimers and their synthesis, focusing on the innovative self-assembly synthesis of supramolecular dendrimers. We then detail the representative examples of the noncovalent supramolecular PAMAM dendrimers established in our group for the delivery of anticancer drugs, nucleic acid therapeutics, and imaging agents, either within the dendrimer interior or at the dendrimer terminals on the surface. Some of the supramolecular dendrimer nanosystems exhibit outstanding performance, excelling the corresponding clinical anticancer therapeutics and imaging agents. This self-assembly approach to creating supramolecular dendrimers is completely novel in concept yet easy to implement in practice, offering a fresh perspective for exploiting the advantageous features of dendrimers in biomedical applications.