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Shape-controlled paclitaxel nanoparticles with multiple morphologies: rod-shaped, worm-like, spherical, and fingerprint-like.

ABSTRACT: Although many nanocarriers have been developed to encapsulate paclitaxel (PTX), the drug loading and circulation time in vivo always are not ideal because of its rigid "brickdust" molecular structure. People usually concentrate their attention on the spherical nanocarriers, here paclitaxel nanoparticles with different geometries were established through the chemical modification of PTX, nanoprecipitation, and core-matched cargos. Previously we have developed rod-shape paclitaxel nanocrystals using block copolymer, pluronic F127. Unfortunately, the pharmacokinetic (PK) profile of PTX nanocrystals is very poor. However, when PTX was replaced by its prodrug, the geometry of the nanoparticles changed from rod-shaped to worm-like. The worm-like nanoparticles can be further changed to spherical nanoparticles using the nanoprecipitation method, and changed to fingerprint-like nanoparticles upon the addition of the core-matched PTX. The nanoparticles with nonspherical morphologies, including worm-like nanoparticles and fingerprint-like nanoparticles, offer significant advantages in regards to key PK parameters in vivo. More important, in this report the application of the core-matching technology in creating a core-matched environment capable of controlling the in vivo PK of paclitaxel was demonstrated, and it revealed a novel technique platform to construct nanoparticles and improve the poor PK profiles of the drugs.

SUBMITTER: Wang Y

PROVIDER: S-EPMC4334274 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Project description:The morphologies of gold nanoparticles (NPs) affect their tumor accumulation through enhanced permeability and retention effect. However, detailed information and mechanisms of NPs' characteristics affecting tumor accumulation are limited. The aim of this study is to evaluate the effects of shape and active targeting ligands of theranostic NPs on tumor accumulation and therapeutic efficacy, and to elucidate the underlying mechanism. Methods: αvβ3 integrin-targeted, cisplatin-loaded and radioisotope iodine-125 labeled spherical and rod-shaped gold nano theranostic probes (RGD-125IPt-AuNPs and RGD-125IPt-AuNRs) with similar sizes were fabricated and characterized. The in vivo distribution and chemo-radio therapeutic efficacy against tumors of these newly developed probes were subsequently evaluated. Moreover, a physiologically based pharmacokinetic (PBPK) model was developed to characterize the in vivo kinetics of these probes at the sub-organ level, and to reveal the mechanism of NPs' shape and active targeting ligands effects on tumor accumulation. Result: Cisplatin and iodine-125 were loaded sequentially onto the NPs through a thin polydopamine coating layer on the NPs. Both RGD-125IPt-AuNPs and RGD-125IPt-AuNRs exhibited high specificity for αvβ3 in vitro, with the rod-shaped probe being more efficient. The PBPK model revealed that rod-shaped gold NPs diffused more rapidly in tumor interstitial than the spherical ones. Tumor accumulations of non-targeted and rod-shaped RAD-125IPt-AuNRs was higher in short term (1 h post injection), but not pronounced and similar to that of non-targeted spherical RAD-125IPt-AuNPs in 24 h after intravenous injection, revealing that the NPs' shape did not have a significant impact on tumor accumulations through enhanced permeability and retention (EPR) effect in long-term. While for actively targeted NPs, in addition to a higher distribution coefficient, RGD-125IPt-AuNRs also had a much higher tumor maximum uptake rate constant than RGD-125IPt-AuNPs, indicating both the shape and active targeting ligands affected the tumor uptake of rod-shaped NPs. As a result, RGD-125IPt-AuNRs had a more effective inhibition of tumor growth than RGD-125IPt-AuNPs by chemo-radiationtherapy. Conclusion: Our study suggests that both the shape and active targeting ligands of gold NPs play important roles on tumor accumulation and chemo-radio therapeutic effect.

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Shape-controlled paclitaxel nanoparticles with multiple morphologies: rod-shaped, worm-like, spherical, and fingerprint-like.

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