pH-triggered dynamic erosive small molecule chlorambucil nano-prodrugs mediate robust oral chemotherapy

Currently,the dynamic erosive small molecule nano-prodrug is of great demand for oral chemotherapy,owing to its precise structure,high drug loading and improved oral bioavailability via overcoming various physiologic barriers in gastrointestinal tract,blood circulation and tumor tissues compared to other oral nanomedicines.Herein,this work highlights the successful development of pH-triggered dynamic erosive small molecule nano-prodrugs based on in vivo significant pH changes,which are synthesized via amide reaction between chlorambucil and star-shaped ortho esters.The precise nano-prodrugs exhibit extraordinarily high drug loading(68.16%),electric neutrality,strong hydrophobicity,and dynamic large-to-small size transition from gastrointestinal pH to tumoral pH.These favorable physicochemical properties can effectively facilitate gastrointestinal absorption,blood circulation stability,tumor accumulation,cellular uptake,and cytotoxicity,therefore achieving high oral relative bioavailability(358.72%)and significant tumor growth inhibition while decreasing side effects.Thus,this work may open a new avenue for robust oral chemotherapy attractive for clinical translation.

Fine-tuning the activation behaviors of ternary modular cabazitaxel prodrugs for efficient and on-target oral anti-cancer therapy

The disulfide bond plays a crucial role in the design of anti-tumor prodrugs due to its exceptional tumor-specific redox responsiveness. However, premature breaking of disulfide bonds is triggered by small amounts of reducing substances (e.g., ascorbic acid, glutathione, uric acid and tea polyphenols) in the systemic circulation. This may lead to toxicity, particularly in oral prodrugs that require more frequent and high-dose treatments. Fine-tuning the activation kinetics of these prodrugs is a promising prospect for more efficient on-target cancer therapies. In this study, disulfide, steric disulfide, and ester bonds were used to bridge cabazitaxel (CTX) to an intestinal lymph vessel-directed triglyceride (TG) module. Then, synthetic prodrugs were efficiently incorporated into self-nanoemulsifying drug delivery system (corn oil and Maisine CC were used as the oil phase and Cremophor EL as the surfactant). All three prodrugs had excellent gastric stability and intestinal permeability. The oral bioavailability of the disulfide bond-based prodrugs (CTX-(C)S-(C)S-TG and CTX-S-S-TG) was 11.5- and 19.1-fold higher than that of the CTX solution, respectively, demonstrating good oral delivery efficiency. However, the excessive reduction sensitivity of the disulfide bond resulted in lower plasma stability and safety of CTX-S-S-TG than that of CTX-(C)S-(C)S-TG. Moreover, introducing steric hindrance into disulfide bonds could also modulate drug release and cytotoxicity, significantly improving the anti-tumor activity even compared to that of intravenous CTX solution at half dosage while minimizing off-target adverse effects. Our findings provide insights into the design and fine-tuning of different disulfide bond-based linkers, which may help identify oral prodrugs with more potent therapeutic efficacy and safety for cancer therapy.

Boosting SN38-based oral chemotherapy to combine reductionbioactivated structured lipid-mimetic prodrug with ascorbic acid

The reduction-responsive disulfide bonds have been widely used as bioactive linkages to facilitate a rapid release of anticancer drugs into tumor cells.However,the activation can be hindered by the kinetics of the thiol-disulfide exchange reactions.Supplementing with an additional reductant is a promising strategy to further boost drug release.Herein,inspired by the specific absorption mechanism of triglyceride fat,structured lipid-mimetic oral prodrugs of 7-ethyl-10-hydroxycamptothecin(SN38)were designed to improve intestinal permeability and bypass the first-pass effect.SN38 prodrugs were prepared into lipid formulations that could self-emulsify into nano-sized particles after entering the gastrointestinal tract.Surprisingly,we found that the oral bioavailability of the prodrug lipid formulation could be up to 2.69-fold higher than that of the parent SN38,indicating an effective oral delivery.In addition,the reduction-responsive disulfide bond was used as a linker,and ascorbic acid(ASC)was coadministrated to further promote the efficient release of SN38 from the prodrug.ASC enhanced the oral antitumor effect of the reduction-responsive oral prodrug and exhibited good safety.In summary,the combination of a structured lipid-mimetic prodrug and ASC was firstly demonstrated to boost the oral chemotherapy effect of the difficult-for-oral chemotherapeutics.