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Synergistic targeting of cell membrane, cytoplasm, and nucleus of cancer cells using rod-shaped nanoparticles.

ABSTRACT: Design of carriers for effective delivery and targeting of drugs to cellular and subcellular compartments is an unmet need in medicine. Here, we report pure drug nanoparticles comprising camptothecin (CPT), trastuzumab (TTZ), and doxorubicin (DOX) to enable cell-specific interactions, subcellular accumulation, and growth inhibition of breast cancer cells. CPT is formulated in the form of nanorods which are coated with TTZ. DOX is encapsulated in the TTZ corona around the CPT nanoparticle. Our results show that TTZ/DOX-coated CPT nanorods exhibit cell-specific internalization in BT-474 breast cancer cells, after which TTZ is recycled to the plasma membrane, leaving CPT nanorods in the perinuclear region and delivering DOX into the nucleus of the cells. The effects of CPT-TTZ-DOX nanoparticles on growth inhibition are synergistic (combination index = 0.17 ± 0.03) showing 10-10?000-fold lower inhibitory concentrations (IC50) compared to those of individual drugs. The design of antibody-targeted pure drug nanoparticles offers a promising design strategy to facilitate intracellular delivery and therapeutic efficiency of anticancer drugs.

SUBMITTER: Barua S

PROVIDER: S-EPMC4128961 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Synergistic targeting of cell membrane, cytoplasm, and nucleus of cancer cells using rod-shaped nanoparticles.

Barua Sutapa S Mitragotri Samir S

ACS nano 20130927 11

Design of carriers for effective delivery and targeting of drugs to cellular and subcellular compartments is an unmet need in medicine. Here, we report pure drug nanoparticles comprising camptothecin (CPT), trastuzumab (TTZ), and doxorubicin (DOX) to enable cell-specific interactions, subcellular accumulation, and growth inhibition of breast cancer cells. CPT is formulated in the form of nanorods which are coated with TTZ. DOX is encapsulated in the TTZ corona around the CPT nanoparticle. Our re ...[more]

PMID: 24053162

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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.

Dataset Information

Synergistic targeting of cell membrane, cytoplasm, and nucleus of cancer cells using rod-shaped nanoparticles.

Publications

Synergistic targeting of cell membrane, cytoplasm, and nucleus of cancer cells using rod-shaped nanoparticles.

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