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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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In vitro characterization of SN-38 prodrug-loaded polymeric nanoparticles. a–e) Transmission electron microscopic (TEM) images of SN-38 prodrugs 6-, 7-, 8-, 12-, and 13-loaded NPs (scale bars=100 nm). f) Size distribution of the prodrug-loaded NPs measured by dynamic light scattering (DLS). Except for 7- and 12-loaded NPs (with average dh≈82 and 20 nm, respectively), the formulations of 6, 8, and 13 produce a superimposable histogram with average dh of ca. 43 nm.
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fig02: In vitro characterization of SN-38 prodrug-loaded polymeric nanoparticles. a–e) Transmission electron microscopic (TEM) images of SN-38 prodrugs 6-, 7-, 8-, 12-, and 13-loaded NPs (scale bars=100 nm). f) Size distribution of the prodrug-loaded NPs measured by dynamic light scattering (DLS). Except for 7- and 12-loaded NPs (with average dh≈82 and 20 nm, respectively), the formulations of 6, 8, and 13 produce a superimposable histogram with average dh of ca. 43 nm.

Mentions: Given the success of nanoprecipitation for SN-38 prodrugs (6, 7, 8, 12, and 13), we next characterized their morphology by transmission electron microscopy (TEM) and dynamic light scattering (DLS) analysis. In TEM images, these NP libraries exhibited homogenous populations of similarly spherical shapes with average diameters of 16–43 nm (Figure 2 a–e). DLS analysis showed the monomodality and narrow size distribution (polydispersity index<0.2) of the prodrug-loaded NPs. Compared to the TEM results, the hydrodynamic diameters (dh) measured by DLS were slightly larger, but all were smaller than 100 nm (Figure 2 f). In particular, prodrug 12 encapsulated NPs had a very small diameter (dh≈20 nm, n=4) compared to the other prodrug-NPs, indicating the formation of more compact core–shell structures. Previous studies suggested that the tumor penetration and accumulation of nanoparticles is highly dependent on the overall size and that nanomedicines in the sub-100 nm range have superior antitumor efficacy in various solid tumors.[11] Therefore, we envisioned that this fabrication technology for SN-38 prodrugs could potentially increase intratumoral delivery.


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)

In vitro characterization of SN-38 prodrug-loaded polymeric nanoparticles. a–e) Transmission electron microscopic (TEM) images of SN-38 prodrugs 6-, 7-, 8-, 12-, and 13-loaded NPs (scale bars=100 nm). f) Size distribution of the prodrug-loaded NPs measured by dynamic light scattering (DLS). Except for 7- and 12-loaded NPs (with average dh≈82 and 20 nm, respectively), the formulations of 6, 8, and 13 produce a superimposable histogram with average dh of ca. 43 nm.
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Related In: Results  -  Collection

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

fig02: In vitro characterization of SN-38 prodrug-loaded polymeric nanoparticles. a–e) Transmission electron microscopic (TEM) images of SN-38 prodrugs 6-, 7-, 8-, 12-, and 13-loaded NPs (scale bars=100 nm). f) Size distribution of the prodrug-loaded NPs measured by dynamic light scattering (DLS). Except for 7- and 12-loaded NPs (with average dh≈82 and 20 nm, respectively), the formulations of 6, 8, and 13 produce a superimposable histogram with average dh of ca. 43 nm.
Mentions: Given the success of nanoprecipitation for SN-38 prodrugs (6, 7, 8, 12, and 13), we next characterized their morphology by transmission electron microscopy (TEM) and dynamic light scattering (DLS) analysis. In TEM images, these NP libraries exhibited homogenous populations of similarly spherical shapes with average diameters of 16–43 nm (Figure 2 a–e). DLS analysis showed the monomodality and narrow size distribution (polydispersity index<0.2) of the prodrug-loaded NPs. Compared to the TEM results, the hydrodynamic diameters (dh) measured by DLS were slightly larger, but all were smaller than 100 nm (Figure 2 f). In particular, prodrug 12 encapsulated NPs had a very small diameter (dh≈20 nm, n=4) compared to the other prodrug-NPs, indicating the formation of more compact core–shell structures. Previous studies suggested that the tumor penetration and accumulation of nanoparticles is highly dependent on the overall size and that nanomedicines in the sub-100 nm range have superior antitumor efficacy in various solid tumors.[11] Therefore, we envisioned that this fabrication technology for SN-38 prodrugs could potentially increase intratumoral delivery.

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