Encapsulating Active Pharmaceutical Ingredients in Self‐Assembling Adamantanes with Short DNA Zippers

Abstract

Formulating pharmaceutically active ingredients for drug delivery is a challenge. There is a need for new drug delivery systems that take up therapeutic molecules and release them into biological systems. We propose a novel mode of encapsulation that involves matrices formed through co‐assembly of drugs with adamantane hybrids that feature four CG dimers as sticky ends. Such adamantanes are accessible via inexpensive solution‐phase syntheses, and the resulting materials show attractive properties for controlled release. This is demonstrated for two different hybrids and a series of drugs, including anticancer drugs, antibiotics, and cyclosporin. Up to 20 molar equivalents of active pharmaceutical ingredients (APIs) are encapsulated in hybrid materials. Encapsulation is demonstrated for DNA‐binding and several non‐DNA binding compounds. Nanoparticles were detected that range in size from 114–835 nm average diameter, and ζ potentials were found to be between −29 and +28 mV. Release of doxorubicin into serum at near‐constant rates for 10 days was shown, demonstrating the potential for slow release. The encapsulation and release in self‐assembling matrices of dinucleotide‐bearing adamantanes appears to be broadly applicable and may thus lead to new drug delivery systems for APIs.

Hybridization Networks of mRNA and Branched RNA Hybrids

“…Either synthesis started from adamantane tetraol ( 1 , dubbed “TOA”), which was reacted with a phosphoramidite building block of uridine for solid‐phase RNA synthesis, using the TBDMS protocol. The aliphatic alcohol was considered unproblematic in terms of possible toxicity, [11] and the arms are entirely made up of unmodified RNA.…”

“…Material formation through multivalent hybridization of the arms of branched DNA hybrids alone, or in combination with connector duplexes featuring sticky ends, has been reported before. [5][6][7][8][9][10][11][12] The underlying multivalent hybridization events usually require shorter duplex lengths than those of linear strands, so that dinucleotides can suffice to induce assembly into a material. [5] Even in light of these earlier findings, the current results are surprising.…”

“…The hybridization networks formed by such species can capture a range of different active pharmaceutical ingredients and release them into serum from the resulting solid. [11] Further, it was recently shown that hybridization networks made up of hybrids and linear duplexes as spacers or binding sites can encapsulate proteins, either by non-specific capture upon precipitation or based on sequence-specific binding events. [12] The resulting hybrid materials can stabilize proteins against denaturation.…”

A Three‐State System Based on Branched DNA Hybrids

“…Our solution‐phases syntheses give functional, monodisperse compounds of up to 10 kDa molecular weight with an unusually high number of “sticky ends” and are easy to scale up. Since branched oligonucleotides have the potential to encapsulate active pharmaceutical ingredients, we are planning to study formulations that are stable at acidic pH, as experienced upon uptake into endosomes, and can release active ingredients at the near‐neutral pH of the cytosol.…”

“…Unlike other DNA‐based materials that are produced from synthetic DNA, the hybrids are inexpensive to prepare, using solution‐phase reactions only . The materials described thus far are formed as precipitates that can take up small molecules as guests, including active pharmaceutical ingredients, but not as hydrogels. Hydrogels based on DNA, including plasmid DNA, have been used as delivery vehicles for insulin, as metamaterials with shape memory, or as a medium for encapsulating quantum dots .…”