Nucleoside Analogue-Based Supramolecular Nanodrugs Driven by Molecular Recognition for Synergistic Cancer Therapy

Abstract

The utilization of nanotechnology for the delivery of a wide range of anticancer drugs has the potential to reduce adverse effects of free drugs and improve the anticancer efficacy. However, carrier materials and/or chemical modifications associated with drug delivery make it difficult for nanodrugs to achieve clinical translation and final Food and Drug Administration (FDA) approvals. We have discovered a molecular recognition strategy to directly assemble two FDA-approved small-molecule hydrophobic and hydrophilic anticancer drugs into well-defined, stable nanostructures with high and quantitative drug loading. Molecular dynamics simulations demonstrate that purine nucleoside analogue clofarabine and folate analogue raltitrexed can self-assemble into stable nanoparticles through molecular recognition. In vitro studies exemplify how the clofarabine:raltitrexed nanoparticles could greatly improve synergistic combination effects by arresting more G1 phase of the cell cycle and reducing intracellular deoxynucleotide pools. More importantly, the nanodrugs increase the blood retention half-life of the free drugs, improve accumulation of drugs in tumor sites, and promote the synergistic tumor suppression property in vivo.

Tough Adhesion of Nucleobase‐Tackifed Gels in Diverse Solvents

“…[23] Briefly, a suspended adenine solution in DMF with triethylamine was continuously stirred in an ice bath for 30 min. The adhesive gels presented a tough adhesion for various substrate surfaces in the air and diverse nonpolar and polar solvents.…”

“…[21][22][23][24] In our previous work, the nucleobase-tackified strategy was presented to successfully endow hydrogels with strong, multipurpose, durable, and antifatigue adhesive behavior only in the air. [21][22][23][24] In our previous work, the nucleobase-tackified strategy was presented to successfully endow hydrogels with strong, multipurpose, durable, and antifatigue adhesive behavior only in the air.…”

Zirconyl Hydrogenphosphate Nanocontainers for Flexible Transport and Release of Lipophilic Cytostatics, Insecticides, and Antibiotics

“…The poor aqueous solubility of lipophilic drugs accounts for severe restrictions in terms of administration (especially intravenously) and transport (especially in blood) . Often insufficient solubility and limited membrane permeability limit the applicability of lipophilic drugs 3d,4,5. To enable intravenous, oral, or gastrointestinal administration, appropriate carrier systems were suggested,3c,6 especially including metal oxide nanoparticles (e.g., SiO 2 , Fe 2 O 3 , MgCO 3 , Ca 3 (PO 4 ) 2 ), polymer nanoparticles (e.g., polyethylene glycol/PEG), biopolymers (e.g., lipids, proteins),3a,9 graphene, as well as micelles,6b,11 nanoemulsions, and liposomes .…”

“…To enable intravenous, oral, or gastrointestinal administration, appropriate carrier systems were suggested,3c,6 especially including metal oxide nanoparticles (e.g., SiO 2 , Fe 2 O 3 , MgCO 3 , Ca 3 (PO 4 ) 2 ), polymer nanoparticles (e.g., polyethylene glycol/PEG), biopolymers (e.g., lipids, proteins),3a,9 graphene, as well as micelles,6b,11 nanoemulsions, and liposomes . Many nanocontainer systems yet suffer from weaknesses such as uncontrolled drug leakage and aggregation of lipophilic drugs, limited cell uptake, high material complexity, unexpected toxicity and hypersensitivity, damage of cell membranes, inadequate drug loading, and poor stability in blood 3c,5a,7b,d,8c,14. Especially, SiO 2 ‐based nanocarriers were described to cause toxic effects 7b,14,15.…”

One pot preparation of polyurethane‐based GSH‐responsive core‐shell nanogels for controlled drug delivery

“…However, how to overcome the undesirable side effects and enhance the drug efficiency is still a major challenge for their clinical applications . For the purpose of more effective and safer cancer treatment, different types of engineered nanomedicine have been designed and prepared based on the development of the nanotechnology and biomaterials in the past decade . Especially, bioresponsive nanomaterial‐based drug delivery systems can response to the tumor physiological environment and release the payloads smartly under the biological stimulus.…”