Emerging concepts in dendrimer-based nanomedicine: from design principles to clinical applications.

Dendrimers are widely recognized as members of the fourth major architectural class of polymers after linear, cross-linked, and branched architectural types. They have become a desirable polymer category for drug delivery applications based on the ability to readily structure control their six “critical nanoscale design parameters” (CNDPs). These CNDPs include (1) size, (2) shape, (3) surface chemistry, (4) flexibility/rigidity, (5) architecture and (6) elemental composition. The poly(amidoamine) dendrimer (PAMAM) family, first reported by Tomalia et al. in 1985, is one of the most widely investigated dendrimer types for drug delivery. Drugs can either be physically entrapped or chemically conjugated onto dendrimers. Association of drugs with dendrimers depends on numerous factors but mainly on dendrimer architecture. PAMAM dendrimers are available with a variety of surface groups, cores, and generations (i.e., sizes); however, drug associations with dendrimers are most dramatically influenced by the dendrimer’s interior composition, generations (i.e., sizes), and surface chemistries. The physical drug-dendrimer associations are often defined by the periodic dendrimer property patterns which are manifested as a function of dendrimer architecture and generations. Engineering the “critical nanoscale design parameters” (CNDPs) of dendrimers provides a systematic strategy for optimizing dendrimer (host) and drug (guest) relationships. This article discusses the role of CNDPs on guest-host drug entrapment in dendrimers by physical or supramolecular means (i.e., a non-conjugation, formulation type approach).

1 - Engineering critical nanoscale design parameters (CNDPs): A strategy for developing effective nanomedicine therapies and assessing quantitative nanoscale structure-activity relationships (QNSARs)

The term dendritic effects has been used extensively by many dendritic polymer scientists since the early 1990s to describe certain intrinsic physico-chemical and application property patterns exhibited by dendrons and dendrimers. Until the present, this terminology has been used to report the dependency of these unique property patterns on dendritic generation levels, thus implying such effects are manifested solely as a function of their architecture and size. This review presents a deeper examination of these issues and shows that essentially all dendritic effects are clearly related to one or more and perhaps the concurrent interaction of several structure controlled parameters referred to as critical nanoscale design parameters (CNDPs). These structure controlled parameters include: (a) size, (b) shape, (c) surface chemistry, (d) flexibility/rigidity, (e) architecture and (f) elemental composition. Furthermore, it has been shown that many dendritic effects are actually architecturally driven as a consequence of congestion involving many of the CNDPs (a–d) and may be categorized into so called: (i) endo- and (ii) exo-type effects. It is noteworthy that Percec/Rosen et al. [J. Am. Chem. Soc., 2009, 131, 17500] have used these same CNDPs to predict many important dendritic effects (i.e., nano-periodic property patterns) leading to the first examples of Mendeleev-type soft matter nano-periodic tables. These soft matter nano-periodic tables provided unprecedented a priori predictions (i.e., 87–93% accuracy) of self-assembly pathways to tertiary and quaternary structures resulting from many libraries of amphiphilic dendrons based solely on the quantized CNDPs present in the dendron primary structures. In conclusion, it appears that dendritic effects as we now know them can be viewed as collections of "mini nano-periodic property patterns" that may ultimately be used to frame and define a broader encompassing Mendeelev-like system for the a priori prediction of dendritic polymer properties.

2 - Dendrimers in drug delivery and the role of “critical nanoscale design parameters” (CNDPs)

Phosphorus-containing dendrimers are defined as dendrimers having at least one phosphorus atom at each branching point. In this review, we will show how phosphorhydrazone dendrimers can be modified at will at the level of the core and of the branches, to afford specific properties, such as fluorescence to image biological events. Accelerated methods of synthesis of phosphorus (one step for one generation) will be also displayed, as well as the specific reactivity of P=N–P=S linkages obtained in most of these accelerated method of synthesis, which has led to particularly original dendritic architectures, such as dendrons included in dendrimers. Finally, we will display how modifications of the internal structure of a series of dendrimers having the same type and number of terminal functions can deeply modify their biological anti-inflammatory properties. Among the six critical nanoscale design parameters (CNDP), we will show how two of them, i.e., architecture and elemental composition, have been particularly engineered to modify phosphorus-containing dendrimers, in order to fulfill the desired properties.

This article proposes a systematic framework for unifying and defining nanoscience based on historic first principles and step logic that led to a “central paradigm” (i.e., unifying framework) for traditional elemental/small-molecule chemistry. As such, a Nanomaterials classification roadmap is proposed, which divides all nanomatter into Category I: discrete, well-defined and Category II: statistical, undefined nanoparticles. We consider only Category I, well-defined nanoparticles which are >90% monodisperse as a function of Critical Nanoscale Design Parameters (CNDPs) defined according to: (a) size, (b) shape, (c) surface chemistry, (d) flexibility, and (e) elemental composition. Classified as either hard (H) (i.e., inorganic-based) or soft (S) (i.e., organic-based) categories, these nanoparticles were found to manifest pervasive atom mimicry features that included: (1) a dominance of zero-dimensional (0D) core–shell nanoarchitectures, (2) the ability to self-assemble or chemically bond as discrete, quantized nanounits, and (3) exhibited well-defined nanoscale valencies and stoichiometries reminiscent of atom-based elements. These discrete nanoparticle categories are referred to as hard or soft particle nanoelements. Many examples describing chemical bonding/assembly of these nanoelements have been reported in the literature. We refer to these hard:hard (H-n:H-n), soft:soft (S-n:S-n), or hard:soft (H-n:S-n) nanoelement combinations as nanocompounds. Due to their quantized features, many nanoelement and nanocompound categories are reported to exhibit well-defined nanoperiodic property patterns. These periodic property patterns are dependent on their quantized nanofeatures (CNDPs) and dramatically influence intrinsic physicochemical properties (i.e., melting points, reactivity/self-assembly, sterics, and nanoencapsulation), as well as important functional/performance properties (i.e., magnetic, photonic, electronic, and toxicologic properties). We propose this perspective as a modest first step toward more clearly defining synthetic nanochemistry as well as providing a systematic framework for unifying nanoscience. With further progress, one should anticipate the evolution of future nanoperiodic table(s) suitable for predicting important risk/benefit boundaries in the field of nanoscience.Electronic supplementary materialThe online version of this article (doi:10.1007/s11051-009-9632-z) contains supplementary material, which is available to authorized users.

This article reviews progress over the past three decades related to the role of dendrimer-based, branch cell symmetry in the development of advanced drug delivery systems, aqueous based compatibilizers/solubilizers/excipients and nano-metal cluster catalysts. Historically, it begins with early unreported work by the Tomalia Group (i.e., The Dow Chemical Co.) revealing that all known dendrimer family types may be divided into two major symmetry categories; namely: Category I: symmetrical branch cell dendrimers (e.g., Tomalia, Vögtle, Newkome-type dendrimers) possessing interior hollowness/porosity and Category II: asymmetrical branch cell dendrimers (e.g., Denkewalter-type) possessing no interior void space. These two branch cell symmetry features were shown to be pivotal in directing internal packing modes; thereby, differentiating key dendrimer properties such as densities, refractive indices and interior porosities. Furthermore, this discovery provided an explanation for unimolecular micelle encapsulation (UME) behavior observed exclusively for Category I, but not for Category II. This account surveys early experiments confirming the inextricable influence of dendrimer branch cell symmetry on interior packing properties, first examples of Category (I) based UME behavior, nuclear magnetic resonance (NMR) protocols for systematic encapsulation characterization, application of these principles to the solubilization of active approved drugs, engineering dendrimer critical nanoscale design parameters (CNDPs) for optimized properties and concluding with high optimism for the anticipated role of dendrimer-based solubilization principles in emerging new life science, drug delivery and nanomedical applications.

This special issue entitled “Functional Dendrimers” focuses on the manipulation of at least six “critical nanoscale design parameters” (CNDPs) of dendrimers including: size, shape, surface chemistry, flexibility/rigidity, architecture and elemental composition. These CNDPs collectively define properties of all “functional dendrimers”. This special issue contains many interesting examples describing the manipulation of certain dendrimer CNDPs to create new emerging properties and, in some cases, predictive nanoperiodic property patterns (i.e., dendritic effects). The systematic engineering of CNDPs provides a valuable strategy for optimizing functional dendrimer properties for use in specific applications.

Two critical nanoscale design parameters (CNDPs); namely, surface chemistry and interior compositions of poly(amidoamine) (PAMAM) dendrimers were systematically engineered to produce unique hyperpolarizable, electro-optical substrates. These electro-optically active dendritic films were demonstrated to produce high quality, continuous wave terahertz radiation when exposed to a suitable pump laser that could be used for spectrometry and molecular imaging. These dendrimer based dipole excitation (DDE) terahertz sources were used to construct a working spectrometer suitable for many practical applications including THz imaging and analysis of encapsulated hydrogen species in fullerenes.

Development of a central paradigm is undoubtedly the single most influential force responsible for advancing Dalton's 19th century atomic/molecular chemistry concepts to the current maturity enjoyed by traditional chemistry. A similar central dogma for guiding and unifying nanoscience has been missing. This review traces the origins, evolution, and current status of such a critical nanoperiodic concept/framework for defining and unifying nanoscience. Based on parallel efforts and a mutual consensus now shared by both chemists and physicists, a nanoperiodic/systematic framework concept has emerged. This concept is based on the well-documented existence of discrete, nanoscale collections of traditional inorganic/organic atoms referred to as hard and soft superatoms (i.e., nanoelement categories). These nanometric entities are widely recognized to exhibit nanoscale atom mimicry features reminiscent of traditional picoscale atoms. All unique superatom/nanoelement physicochemical features are derived from quantized structural control defined by six critical nanoscale design parameters (CNDPs), namely, size, shape, surface chemistry, flexibility/rigidity, architecture, and elemental composition. These CNDPs determine all intrinsic superatom properties, their combining behavior to form stoichiometric nanocompounds/assemblies as well as to exhibit nanoperiodic properties leading to new nanoperiodic rules and predictive Mendeleev-like nanoperiodic tables, and they portend possible extension of these principles to larger quantized building blocks including meta-atoms.

It was A. Lavoisier's original thinking in Traite Elementaire de Chemie (1789) followed by J. Dalton's seminal "atom/molecular hypothesis" (i.e., New System of Chemical Philosophy, 1808) that defined "first principles" for much of our contemporary small molecule chemistry. Dalton's concept, advocating atom-based (elemental) building blocks (0.1–0.6 nm) for the synthesis of well defined small molecules, has emerged as a fundamental theme over the past 200 years. It initiated fundamental concepts such as well defined mass combining ratios, stoichiometries, valency and compound formation which have defined the "central dogma" and underpinned the traditional fields of both organic/polymer and inorganic sciences. As such, these historical examples portend the significant role that similar well defined, quantized soft nano-matter, modules such as dendrons and dendrimers (1.0–20 nm) might be expected to play in the emerging science of nano-syntheses. Dendrimers are well defined collections of atoms that may be viewed as core-shell type atom mimics (i.e., soft nano-element like modules). More than 12,000 published references in the dendrimer field have clearly demonstrated the ability to structure control important Critical Nanoscale Design Parameters (CNDPs) such as: (a) size, (b) shape, (c) surface chemistry, (d) flexibility and (e) architecture over a wide range of structures and compositions. These are features shared with elemental atoms and account for unique atom-like combining properties exhibited by dendrimers to yield well defined nano-module stoichiometries. We report first steps, including many literature examples that demonstrate the construction of well defined soft-soft and soft-hard matter nano-compounds. A variety of dendrimer surface reactions or guest-host assemblies have been shown to produce stoichiometric nano-compounds such as: (a) dendrimer-dendrimer, (b) dendrimer-protein (c) dendrimer-fullerene and dendrimer-metal nanocluster structures, to mention a few. These literature examples provide compelling evidence for the emergence of an active dendron and dendrimer module based synthetic nano-chemistry platform.

Optical Molecular Imaging Approaches in Colorectal Cancer

Optical properties of natural small molecules and their applications in imaging and nanomedicine.

Milk exosomes: Nature's abundant nanoplatform for theranostic applications

Peptides have become an indispensable tool in engineering of multifunctional nanostructure platforms for biomedical applications such as targeted drug and gene delivery, imaging and biosensing. They can be covalently incorporated into a variety of nanoparticles (NPs) including polymers, metallic nanoparticles, and others. Using different bioconjugation techniques, multifunctional peptide-modified NPs can be formulated to produce therapeutical and diagnostic platforms offering high specificity, lower toxicity, biocompatibility, and stimuli responsive behavior. Targeting peptides can direct the nanoparticles into specific tissues for targeted drug and gene delivery and imaging applications due to their specificity towards certain receptors. Furthermore, due to their stimuli-responsive features, they can offer controlled release of therapeutics into desired sites of disease. In addition, peptide-based biosensors and imaging agents can provide non-invasive detection and monitoring of diseases including cancer, infectious diseases, and neurological disorders. In this review, we covered the design and formulation of recent peptide-based NP platforms, as well as their utilization in in vitro and in vivo applications such as targeted drug and gene delivery, targeting, sensing, and imaging applications. In the end, we provided the future outlook to design new peptide conjugated nanomaterials for biomedical applications.