Concepts of nanoparticle cellular uptake, intracellular trafficking, and kinetics in nanomedicine.

Among the many challenges in medicine, the treatment and cure of cancer remains an outstanding goal given the complexity and diversity of the disease. Nanotheranostics, the integration of therapy and diagnosis in nanoformulations, is the next generation of personalized medicine to meet the challenges in precise cancer diagnosis, rational management and effective therapy, aiming to significantly increase the survival rate and improve the life quality of cancer patients. Different from most conventional platforms with unsatisfactory theranostic capabilities, supramolecular cancer nanotheranostics have unparalleled advantages in early-stage diagnosis and personal therapy, showing promising potential in clinical translations and applications. In this review, we summarize the progress of supramolecular cancer nanotheranostics and provide guidance for designing new targeted supramolecular theranostic agents. Based on extensive state-of-the-art research, our review will provide the existing and new researchers a foundation from which to advance supramolecular cancer nanotheranostics and promote translationally clinical applications.

Supramolecular cancer nanotheranostics

SELEX methods on the road to protein targeting with nucleic acid aptamers.

It is crucial to deliver anticancer drugs to target cells with high precision and efficiency. While nanomaterials have been shown to enhance the delivery efficiency once they reach the target, it remains challenging for precise drug delivery to overcome the nonspecific adsorption and off-target effect. To meet this challenge, we report herein the design of a novel DNA nanostructure to act as a DNA nanoscale precision-guided missile (D-PGM) for highly efficient loading and precise delivery of chemotherapeutic agents to specific target cells. The D-PGM consists of two parts: a warhead (WH) and a guidance/control (GC). The WH is a rod-like DNA nanostructure as a drug carrier, whose trunk is a three-dimensionally self-assembled DNA nanoscale architecture from the programmed hybridization among two palindromic DNA sequences in the x-y dimension and two common DNA oligonucleotides in the z direction, making the WH possess a high payload capacity of drugs. The GC is an aptamer-based logic gate assembled in a highly organized fashion capable of performing cell-subtype-specific recognition via the sequential disassembly, mediated by cell-anchored aptamers. Because of the cooperative effects between the WH and the GC, the GC logic gates operate like the guidance and control system in a precision-guided missile to steer the doxorubicin (DOX)-loaded DNA WH toward target cancer cells, leading to selective and enhanced therapeutic efficacy. Moreover, fluorophores attached to different locations of D-PGM and DOX fluorescence dequenching upon release enable intracellular tracing of the DNA nanostructures and drugs. The results demonstrate that by mimicking the functionalities of a military precision-guided missile to design the sequential disassembly of the GC system in multistimuli-responsive fashion, our intrinsically biocompatible and degradable D-PGM can accurately identify target cancer cells in complex biological milieu and achieve active targeted drug delivery. The success of this strategy paves the way for specific cell identity and targeted cancer therapy.

Precision-Guided Missile-Like DNA Nanostructure Containing Warhead and Guidance Control for Aptamer-Based Targeted Drug Delivery into Cancer Cells in Vitro and in Vivo

Light is a particularly appealing tool for on-demand drug delivery due to its noninvasive nature, ease of application and exquisite temporal and spatial control. Great progress has been achieved in the development of novel light-driven drug delivery strategies with both breadth and depth. Light-controlled drug delivery platforms can be generally categorized into three groups: photochemical, photothermal, and photoisomerization-mediated therapies. Various advanced materials, such as metal nanoparticles, metal sulfides and oxides, metal-organic frameworks, carbon nanomaterials, upconversion nanoparticles, semiconductor nanoparticles, stimuli-responsive micelles, polymer- and liposome-based nanoparticles have been applied for light-stimulated drug delivery. In view of the increasing interest in on-demand targeted drug delivery, we review the development of light-responsive systems with a focus on recent advances, key limitations, and future directions.

Light: A Magical Tool for Controlled Drug Delivery.

Platforms for targeted drug-delivery must simultaneously exhibit serum stability, efficient directed cell internalization, and triggered drug release. Here, using lipid-mediated self-assembly of aptamers, we combine multiple structural motifs into a single nanoconstruct that targets hepatocyte growth factor receptor (cMet). The nanocarrier consists of lipidated versions of a cMet-binding aptamer and a separate lipidated GC-rich DNA hairpin motif loaded with intercalated doxorubicin. Multiple 2',6'-dimethylazobenzene moieties are incorporated into the doxorubicin-binding motif to trigger the release of the chemotherapeutics by photoisomerization. The lipidated DNA scaffolds self-assemble into spherical hybrid-nanoconstructs that specifically bind cMet. The combined features of the nanocarriers increase serum nuclease resistance, favor their import into cells presumably mediated by endocytosis, and allow selective photo-release of the chemotherapeutic into the targeted cells. cMet-expressing H1838 tumor cells specifically internalize drug-loaded nanoconstructs, and subsequent UV exposure enhances cell mortality. This modular approach thus paves the way for novel classes of powerful aptamer-based therapeutics.

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Supramolecular aptamer nano-constructs for receptor-mediated targeting and light-triggered release of chemotherapeutics into cancer cells.

The present invention relates to a nucleic acid-based assembly comprising: at least one nucleic acid aptamer, and at least one nucleic acid motif designed to physically capture a drug. The nucleic acid motif may comprise one or more photo-responsive moieties that effect the release of the drug upon irradiation. The aptamer and the nucleic acid motif each can be covalently linked to one or more lipids, and the lipid- modified aptamer and nucleic acid motif may form the assembly through noncovalent interaction. The invention further relates to use of the nucleic acid-based assembly in the treatment of cancer.

Nucleic acid-based assembly and use thereof in cancer therapy

The present invention relates to a nucleic acid-based assembly comprising: at least one nucleic acid aptamer, and at least one nucleic acid motif designed to physically capture a drug, wherein the nucleic acid motif comprises one or more photo-responsive moieties that effect the release of the drug upon irradiation, wherein the aptamer and the nucleic acid motif each are covalently linked to one or more lipids, wherein the lipid-modified aptamer and nucleic acid motif form the assembly through noncovalent interaction. The invention further relates to use of the nucleic acid-based assembly in the treatment of cancer.

Stephan Irsen

Papers

Supramolecular aptamer nano-constructs for receptor-mediated targeting and light-triggered release of chemotherapeutics into cancer cells.

Nucleic acid-based assembly and use thereof in cancer therapy

Nucleic acid-based assembly and use of the assembly in cancer therapy