SignificanceNanotechnology-based imaging is expected to bring breakthroughs in cancer diagnosis by improving imaging sensitivity and specificity while reducing toxicity. Here, we developed an innovative nanosystem for positron emission tomography (PET) imaging based on a self-assembling amphiphilic dendrimer. This dendrimer assembled spontaneously into uniform supramolecular nanomicelles with abundant PET reporting units on the surface. By harnessing both dendrimeric multivalence and the “enhanced permeation and retention” (EPR) effect, this dendrimer nanosystem effectively accumulated in tumors, leading to exceedingly sensitive and specific imaging of various tumors, especially those that are otherwise undetectable using the clinical gold reference 2-fluorodeoxyglucose ([18F]FDG). This study illustrates the power of nanotechnology based on self-assembling dendrimers to provide an effective platform for bioimaging and related biomedical applications.
Conspectus
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.
The alarming and prevailing antibiotic resistance crisis urgently calls for innovative “outside of the box” antibacterial agents, which can differ substantially from conventional antibiotics.
Bioimaging has revolutionized medicine by providing accurate information for disease diagnosis and treatment. Nanotechnology‐based bioimaging is expected to further improve imaging sensitivity and specificity. In this context, supramolecular nanosystems based on self‐assembly of amphiphilic dendrimers for single photon emission computed tomography (SPECT) bioimaging are developed. These dendrimers bear multiple In3+ radionuclides at their terminals as SPECT reporters. By replacing the macrocyclic 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid cage with the smaller 1,4,7‐triazacyclononane‐1,4,7‐triacetic acid scaffold as the In3+ chelator, the corresponding dendrimer exhibits neutral In3+‐complex terminals in place of negatively charged In3+‐complex terminals. This negative‐to‐neutral surface charge alteration completely reverses the zeta‐potential of the nanosystems from negative to positive. As a consequence, the resulting SPECT nanoprobe generates a highly sought‐after biodistribution profile accompanied by a drastically reduced uptake in liver, leading to significantly improved tumor imaging. This finding contrasts with current literature reporting that positively charged nanoparticles have preferential accumulation in the liver. As such, this study provides new perspectives for improving the biodistribution of positively charged nanosystems for biomedical applications.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.