Structure-based rational design of prodrugs to enable their combination with polymeric nanoparticle delivery platforms for enhanced antitumor efficacy.
Bottom Line: Here, we employed a drug reform strategy to construct a small library of SN-38 (7-ethyl-10-hydroxycamptothecin)-derived prodrugs, in which the phenolate group was modified with a variety of hydrophobic moieties.This esterification fine-tuned the polarity of the SN-38 molecule and enhanced the lipophilicity of the formed prodrugs, thereby inducing their self-assembly into biodegradable poly(ethylene glycol)-block-poly(d,l-lactic acid) (PEG-PLA) nanoparticulate structures.Our strategy combining the rational engineering of prodrugs with the pre-eminent features of conventionally used polymeric materials should open new avenues for designing more potent drug delivery systems as a therapeutic modality.
Affiliation: First Affiliated Hospital, School of Medicine, Zhejiang University, Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, 310003 (PR China).Show MeSH
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Mentions: To establish the clinical translation potential of prodrug-encapsulated NPs, we performed therapeutic studies in vivo using a HCT-116 colorectal xenograft model. To decrease the number of required animals, only prodrug 6-, 7-, 8-, 12-, and 13-loaded NPs were tested and compared due to their high in vitro activities and stability of formulation. Unfortunately, the 13-formulated NP caused immediate death of mice during intravenous injection; we thus terminated the in vivo therapeutic procedure. The antitumor efficacy of 6-, 7-, 8-, and 12-loaded NPs is illustrated in Figure 4 a, c and d. The tumor growth was remarkably inhibited after the successive intravenous injection of all prodrug-loaded NPs (at 10 mg kg−1 SN-38 equivalent dose) as compared to saline and CPT-11 (12 mg kg−1) controls, thus demonstrating the superiority of combining the drug reform strategy with nanoparticle-based delivery platforms. In particular, the group treated with prodrug 12-loaded NPs produced a more drastic decrease in the tumor progression, resulting in a mean tumor volume of 215 mm3 versus 708 mm3 for CPT-11-treated control (n=7, p<0.01). By comparison, untreated mice from the saline group showed rapid tumor growth, with tumor volume reaching approximately 1293 mm3 by day 20. The in vivo distribution of drugs and consequently of their antitumor efficacies rely heavily on factors such as the nanoparticle size, surface characteristics, and shape. Considering the similar surface properties of the prodrug-encapsulated NPs (e.g., shapes and zeta potentials), we might partially attribute the superior outcome of 12-loaded NPs to their higher cytotoxicity in vitro and relatively small particle size (approximately 20 nm), which exceeds the 5 nm cutoff for clearance by the kidney but may exhibit preferential accumulation in the tumor site. It was also notable that the in vivo efficacy of the prodrug-formulated NPs was closely correlated with their in vitro cytotoxicity, highlighting the value of using this parameter in designing more efficient chemotherapeutics in future work.
Affiliation: First Affiliated Hospital, School of Medicine, Zhejiang University, Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, Key Laboratory of Organ Transplantation, Zhejiang Province, Hangzhou, 310003 (PR China).