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Structure-based rational design of prodrugs to enable their combination with polymeric nanoparticle delivery platforms for enhanced antitumor efficacy.

Wang H, Xie H, Wu J, Wei X, Zhou L, Xu X, Zheng S - Angew. Chem. Int. Ed. Engl. (2014)

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.

View Article: PubMed Central - PubMed

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).

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a) Prodrugs were engineered for combination with amphiphilic copolymer-based nanoparticulate drug delivery platforms. b) Structures of a small library of SN-38 prodrugs. A variety of hydrophobic moieties were conjugated to the 10-hydroxy group through the formation of phenyl ether (1) or ester (2–15) bonds. c) Assessment of the stability of the prodrug-encapsulated, self-assembled PEG-PLA nanoparticles (PEG-PLA/prodrug weight ratios fixed at 20:1).
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fig01: a) Prodrugs were engineered for combination with amphiphilic copolymer-based nanoparticulate drug delivery platforms. b) Structures of a small library of SN-38 prodrugs. A variety of hydrophobic moieties were conjugated to the 10-hydroxy group through the formation of phenyl ether (1) or ester (2–15) bonds. c) Assessment of the stability of the prodrug-encapsulated, self-assembled PEG-PLA nanoparticles (PEG-PLA/prodrug weight ratios fixed at 20:1).

Mentions: Motivated by this rationale, we set out to design and synthesize a small library of novel SN-38 derivatives with the phenolate group on SN-38 shielded by a variety of hydrophobic moieties aimed at enhancing the drug lipophilicity. Sufficient lipophilicity imparted by these moieties would be expected to drive these prodrugs into assembling into the hydrophobic core of NPs in an aqueous environment (Figure 1 a and b). Specifically, we systematically studied these prodrugs for their loading capacity, stability, and release kinetics using a model PEG-PLA material system. The prodrug-loaded NPs exhibited a sustained release profile and exerted cytotoxic activity against each tested cell line upon hydrolysis of the phenyl ester. Furthermore, we showed that the optimized prodrug nanoformulations can be exploited to achieve a high therapeutic index in a human colorectal tumor xenograft model.


Structure-based rational design of prodrugs to enable their combination with polymeric nanoparticle delivery platforms for enhanced antitumor efficacy.

Wang H, Xie H, Wu J, Wei X, Zhou L, Xu X, Zheng S - Angew. Chem. Int. Ed. Engl. (2014)

a) Prodrugs were engineered for combination with amphiphilic copolymer-based nanoparticulate drug delivery platforms. b) Structures of a small library of SN-38 prodrugs. A variety of hydrophobic moieties were conjugated to the 10-hydroxy group through the formation of phenyl ether (1) or ester (2–15) bonds. c) Assessment of the stability of the prodrug-encapsulated, self-assembled PEG-PLA nanoparticles (PEG-PLA/prodrug weight ratios fixed at 20:1).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4225468&req=5

fig01: a) Prodrugs were engineered for combination with amphiphilic copolymer-based nanoparticulate drug delivery platforms. b) Structures of a small library of SN-38 prodrugs. A variety of hydrophobic moieties were conjugated to the 10-hydroxy group through the formation of phenyl ether (1) or ester (2–15) bonds. c) Assessment of the stability of the prodrug-encapsulated, self-assembled PEG-PLA nanoparticles (PEG-PLA/prodrug weight ratios fixed at 20:1).
Mentions: Motivated by this rationale, we set out to design and synthesize a small library of novel SN-38 derivatives with the phenolate group on SN-38 shielded by a variety of hydrophobic moieties aimed at enhancing the drug lipophilicity. Sufficient lipophilicity imparted by these moieties would be expected to drive these prodrugs into assembling into the hydrophobic core of NPs in an aqueous environment (Figure 1 a and b). Specifically, we systematically studied these prodrugs for their loading capacity, stability, and release kinetics using a model PEG-PLA material system. The prodrug-loaded NPs exhibited a sustained release profile and exerted cytotoxic activity against each tested cell line upon hydrolysis of the phenyl ester. Furthermore, we showed that the optimized prodrug nanoformulations can be exploited to achieve a high therapeutic index in a human colorectal tumor xenograft model.

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.

View Article: PubMed Central - PubMed

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
Related in: MedlinePlus