Self‐Assembling Prodrugs by Precise Programming of Molecular Structures that Contribute Distinct Stability, Pharmacokinetics, and Antitumor Efficacy

Abstract

The availability of precisely modulated chemical modifi cations dramatically affects the physicochemical properties of pristine drugs and should facilitate the amphiphilic self-assembly of prodrugs into supramolecular nanoprodrugs (SNPs). However, rationally designing such prodrugs to achieve favorable clinical outcomes still remains a challenge. Here, a library of prodrugs through site-specifi c attachment of a variety of lipophilic moieties to the antitumor agent SN-38 (7-ethyl-10-hydroxycamptothecin) is constructed. Taking advantage of the role of hydroxyl groups as solvophilic moieties, these prodrugs exhibit self-assembly in aqueous environments, allowing for the identifi cation of fi ve prodrugs capable of self-assembling into SNPs at high drug concentrations. Importantly, in vivo studies demonstrate that the antitumor activity of the SNPs correlates well with their stability and long-term circulation. In addition, the modular feature of this SNP design strategy offers the opportunity to readily incorporate additional valuable functionalities (e.g., tumor-specifi c targeting ligands) to the particle surface, which is further exploited to improve antitumor effi cacy in mouse xenograft models. Thus, this structure-based reconstruction of SN-38 molecules signifi cantly improves the potency of SNPs for clinical use. These results also provide novel mechanistic insights into the rational design of prodrugs.

New Generation Nanomedicines Constructed from Self-Assembling Small-Molecule Prodrugs Alleviate Cancer Drug Toxicity

“…By exploiting the innate hydrophobicity of therapeutics, various amphiphilic prodrugs covalently coupled with hydrophilic motifs [e.g., oligo(ethylene glycol) (17)(18)(19), polypeptides (20,21), and copolymers (22)(23)(24)(25)] have been leveraged to mimic the self-assembly behavior that ubiquitously occurs in nature. More intriguingly, several groups, including us, have recently demonstrated that the attachment of lipophilic moieties to anticancer agents conferred the prodrug amphiphiles with the ability to form colloidally stable nanoaggregates rather than precipitants, despite the enhanced overall lipophilicity of prodrugs (26)(27)(28)(29)(30)(31). The above strategy, which is capable of recapitulating the self-assembly process, is unprecedented and should be practical for the facile fabrication of useful nanotherapeutics.…”

Self-assembling prodrugs

“…One interesting, and rather unexpected, report by Couvreur and co-workers showed that squalenoylation of the hydrophobic drug PTX could also allow nanoparticle formation. 134 This was attributed to the flexible nature of the polyunsaturated squalene chain granting an enthalpic benefit during aggregation, and is similar to an effect seen in a later study regarding lipidated SN-38 conjugates by Wang et al 147 In Couvreur’s report, 134 a range of linkers were utilized to connect the two moieties, and all SQ-PTX conjugates showed the ability to aggregate into nanoparticles through nanoprecipitation in water. Their findings showed the ability to control release through molecular design: using a direct ester bond between the paclitaxel and squalenoyl moiety displayed the highest particle stability in comparison to using a succinate linker or diglycolate linker which showed a sequential decrease in stability.…”

A facile route to form self-carried redox-responsive vorinostat nanodrug for effective solid tumor therapy

“…2 Human plasma was provided by Qilu hospital (Jinan, People's Republic of China). This study was approved by the Research Ethics Committee of Qilu Hospital, Shandong University.…”

“…Nuclear Magnetic Resonance Preparation of saha-s-s-Ve NPs and saha-s-s-Ve/TPgs NPs SAHA-S-S-VE NPs were prepared by nano-precipitation according to the reported method. 2,8 Prodrugs were dissolved in dimethyl sulphoxide (DMSO) (50 mg/mL). Then 100 µL was added dropwise to 900 µL ddH2O, under mechanical stirring (800 rpm) at room temperature, to obtain a final concentration of 5 mg/mL prodrug.…”

“…SMND includes amphiphilic self-assembly nanodrug, [1][2][3] nanocrystallized or template-assisted nanodrug, [4][5][6][7] disulfide-induced self-assembled nanodrug, [8][9][10] and so on. It has attracted great interest as a desirable strategy, because of its unique properties in increased chemical stability and solubility, high drug loading, economical fabrication, relative "green" nanoformulation.…”