The application of nanotechnology in medicine and pharmaceuticals is a rapidly advancing field that is quickly gaining acceptance and recognition as an independent area of research called "nanomedicine". Urgent needs in this field, however, are biocompatible and bioactive materials for antifouling surfaces and nanoparticles for drug delivery. Therefore, extensive attention has been given to the design and development of new macromolecular structures. Among the various polymeric architectures, dendritic ("treelike") polymers have experienced an exponential development due to their highly branched, multifunctional, and well-defined structures. This Review describes the diverse syntheses and biomedical applications of dendritic polyglycerols (PGs). These polymers exhibit good chemical stability and inertness under biological conditions and are highly biocompatible. Oligoglycerols and their fatty acid esters are FDA-approved and are already being used in a variety of consumer applications, e.g., cosmetics and toiletries, food industries, cleaning and softening agents, pharmaceuticals, polymers and polymer additives, printing photographing materials, and electronics. Herein, we present the current status of dendritic PGs as functional dendritic architectures with particular focus on their application in nanomedicine, in drug, dye, and gene delivery, as well as in regenerative medicine in the form of non-fouling surfaces and matrix materials.

Nanotechnology has resulted in materials that have greatly improved the effectiveness of drug delivery because of their ability to control matter on the nanoscale. Advanced forms of nanomedicine have been synthesized for better pharmacokinetics to obtain higher efficacy, less systemic toxicity, and better targeting. These criteria have long been the goal in nanomedicine, in particular, for systemic applications in oncological disorders. Now, the "holy grail" in nanomedicine is to design and synthesize new advanced macromolecular nanocarriers and to translate them from lab to clinic. This review describes the current and future perspectives of nanomedicine with particular emphasis on the clinical targets in cancer and inflammation. The advanced forms of liposomes and polyethylene glycol (PEG) based nanocarriers, as well as dendritic polymer conjugates will be discussed with particular attention paid to designs, synthetic strategies, and chemical pathways. In this critical review, we also report on the current status and perspective of dendritic polymer nanoconjugate platforms (e.g. polyamidoamine dendrimers and dendritic polyglycerols) for cellular localization and targeting of specific tissues (192 references).

This paper uses a combined experimental and theoretical approach to gain unique insight into gene delivery. We report the synthesis and investigation of a new family of second-generation dendrons with four triamine surface ligands capable of binding to DNA, degradable aliphatic-ester dendritic scaffolds, and hydrophobic units at their focal points. Dendron self-assembly significantly enhances DNA binding as monitored by a range of experimental methods and confirmed by multiscale modeling. Cellular uptake studies indicate that some of these dendrons are highly effective at transporting DNA into cells (ca. 10 times better than poly(ethyleneimine), PEI). However, levels of transgene expression are relatively low (ca. 10% of PEI). This indicates that these dendrons cannot navigate all of the intracellular barriers to gene delivery. The addition of chloroquine indicates that endosomal escape is not the limiting factor in this case, and it is shown, both experimentally and theoretically, that gene delivery can be correlated with the ability of the dendron assemblies to release DNA. Mass spectrometric assays demonstrate that the dendrons, as intended, do degrade under biologically relevant conditions over a period of hours. Multiscale modeling of degraded dendron structures suggests that complete dendron degradation would be required for DNA release. Importantly, in the presence of the lower pH associated with endosomes, or when bound to DNA, complete degradation of these dendrons becomes ineffective on the transfection time scale-we propose this explains the poor transfection performance of these dendrons. As such, this paper demonstrates that taking this kind of multidisciplinary approach can yield a fundamental insight into the way in which dendrons can navigate barriers to cellular uptake. Lessons learned from this work will inform future dendron design for enhanced gene delivery.

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New targets for RNA interference (RNAi)-based cancer therapy are constantly emerging from the increasing knowledge on key molecular pathways that are paramount for carcinogenesis. Nevertheless, in vivo delivery of small interfering RNA (siRNA) remains a crucial challenge for therapeutic success. siRNAs on their own are not taken up by most mammalian cells in a way that preserves their activity. Moreover, when applied in vivo, siRNA-based approaches are all limited by poor penetration into the target tissue and low silencing efficiency. To circumvent these limitations, we have developed novel polymerized polyglycerol-based dendrimer core shell structures to deliver siRNA to tumors in vivo. These cationic dendrimers can strongly improve the stability of the siRNA, its intracellular trafficking, its silencing efficacy, and its accumulation in the tumor environment owing to the enhanced permeability and retention effect. Here, we show that our dendritic nanocarriers exhibited low cytotoxicity and high efficacy in delivering active siRNA into cells. With use of human glioblastoma and murine mammary adenocarcinoma cell lines as model systems, these siRNA-dendrimer polyplexes silenced the luciferase gene, ectopically overexpressed in these cells. Importantly, significant gene silencing was accomplished in vivo within 24 h of treatment with our luciferase siRNA-nanocarrier polyplexes, as measured by noninvasive intravital bioluminescence imaging. Moreover, our siRNA-nanocarriers show very low levels of toxicity as no significant weight loss was observed after intravenous administration of the polyplexes. We show a proof of concept for siRNA delivery in vivo using a luciferase-based model. We predict that in vivo silencing of important cell growth and angiogenesis regulator genes in a selective manner will justify this approach as a successful anticancer therapy.