A drug-specific nanocarrier design for efficient anticancer therapy

Abstract

The drug-loading properties of nanocarriers depend on the chemical structures and properties of their building blocks. Here, we customize telodendrimers (linear-dendritic copolymer) to design a nanocarrier with improved in vivo drug delivery characteristics. We do a virtual screen of a library of small molecules to identify the optimal building blocks for precise telodendrimer synthesis using peptide chemistry. With rationally designed telodendrimer architectures, we then optimize the drug binding affinity of a nanocarrier by introducing an optimal drug-binding molecule (DBM) without sacrificing the stability of the nanocarrier. To validate the computational predictions, we synthesize a series of nanocarriers and evaluate systematically for doxorubicin delivery. Rhein-containing nanocarriers have sustained drug release, prolonged circulation, increased tolerated dose, reduced toxicity, effective tumor targeting and superior anticancer effects owing to favourable doxorubicin-binding affinity and improved nanoparticle stability. This study demonstrates the feasibility and versatility of the de novo design of telodendrimer nanocarriers for specific drug molecules, which is a promising approach to transform nanocarrier development for drug delivery.

Riboflavin-containing telodendrimer nanocarriers for efficient doxorubicin delivery: High loading capacity, increased stability, and improved anticancer efficacy

“…[43] Riboflavin (Rf, vitamin B2) was identified as one of the top DBMs for DOX binding via both hydrophobic π-π stacking and hydrogen bonding. [43] Rf is the functional fragment in flavin mononucleotide (FMN) and Flavin adenine dinucleotide (FAD), which are cofactors in numerous enzymes for metabolic energy transformation.…”

“…[43] Riboflavin (Rf, vitamin B2) was identified as one of the top DBMs for DOX binding via both hydrophobic π-π stacking and hydrogen bonding. [43] Rf is the functional fragment in flavin mononucleotide (FMN) and Flavin adenine dinucleotide (FAD), which are cofactors in numerous enzymes for metabolic energy transformation. [44] It was reported that the interactions between DOX and Rf are much stronger than the self-association of FAD or FMN and are comparable to DOX-DOX binding.…”

“…[48] All these preclinical and clinical evidence further confirm the strong DOX-Rf interactions as revealed in our computational predictions. [43] Rf has both aromatic structure and hydrophilic ribityl hydroxyls, which share the common features with many hydrotropic compounds used in drug formulations to improve drug solubility. [49] Polymer micelles, composed of such hydrotropic compounds[50] or featured with both polar (H-bonding and dipole-dipole interactions) and hydrophobic interactions [51–53] in the core microenvironment, have been developed to improve loading capacity and stability for efficient drug delivery.…”

“…For example, a facial amphiphilic cholic acid (CA) has been demonstrated to be critical in stabilizing nanocarriers as co-building blocks in TDs, which were decorated with hydrophobic DBMs for the delivery of specific drugs. [43, 54–56] Therefore, the application of Rf affords the TD system with a triple attributes for DOX delivery: (a) enhancing DOX binding affinity; (b) stabilizing nanoformulations; and (c) simplifying TD synthesis as the only building block needed. Unlike the free Rf, the conjugated Rf in TD won’t interfere the activity of DOX after drug release.…”

Thermodynamic and kinetic characterization of pH-dependent interactions between bovine serum albumin and ibuprofen in 2D and 3D systems

“…Nanoscale drug delivery systems have been under investigations for several decades [1][2][3]. At present, numerous types of NPs are designed as feasible candidates for gene therapy and molecular imaging [4], but only very few have actually to mature to clinical applications.…”