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Metallofullerene nanoparticles circumvent tumor resistance to cisplatin by reactivating endocytosis.

ABSTRACT: Cisplatin is a chemotherapeutic drug commonly used in clinics. However, acquired resistance confines its application in chemotherapeutics. To overcome the acquired resistance to cisplatin, it is reasoned, based on our previous findings of mediation of cellular responses by [Gd@C(82)(OH)(22)](n) nanoparticles, that [Gd@C(82)(OH)(22)](n) may reverse tumor resistance to cisplatin by reactivating the impaired endocytosis of cisplatin-resistant human prostate cancer (CP-r) cells. Here we report that exposure of the CP-r PC-3-luc cells to cisplatin in the presence of nontoxic [Gd@C(82)(OH)(22)](n) not only decreased the number of surviving CP-r cells but also inhibited growth of the CP-r tumors in athymic nude mice as measured by both optical and MRI. Labeling the CP-r PC-3 cells with transferrin, an endocytotic marker, demonstrated that pretreatment of the CP-r PC-3-luc cells with [Gd@C(82)(OH)(22)](n) enhanced intracellular accumulation of cisplatin and formation of cisplatin-DNA adducts by restoring the defective endocytosis of the CP-r cancer cells. The results suggest that [Gd@C(82)(OH)(22)](n) nanoparticles overcome tumor resistance to cisplatin by increasing its intracellular accumulation through the mechanism of restoring defective endocytosis. The technology can be extended to other challenges related to multidrug resistance often found in cancer treatments.

SUBMITTER: Liang XJ

PROVIDER: S-EPMC2867714 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Metallofullerene nanoparticles circumvent tumor resistance to cisplatin by reactivating endocytosis.

Liang Xing-Jie XJ Meng Huan H Wang Yingze Y He Haiyong H Meng Jie J Lu Juan J Wang Paul C PC Zhao Yuliang Y Gao Xueyun X Sun Baoyun B Chen Chunying C Xing Genmei G Shen Dingwu D Gottesman Michael M MM Wu Yan Y Yin Jun-Jie JJ Jia Lee L

Proceedings of the National Academy of Sciences of the United States of America 20100405 16

Cisplatin is a chemotherapeutic drug commonly used in clinics. However, acquired resistance confines its application in chemotherapeutics. To overcome the acquired resistance to cisplatin, it is reasoned, based on our previous findings of mediation of cellular responses by [Gd@C(82)(OH)(22)](n) nanoparticles, that [Gd@C(82)(OH)(22)](n) may reverse tumor resistance to cisplatin by reactivating the impaired endocytosis of cisplatin-resistant human prostate cancer (CP-r) cells. Here we report that ...[more]

PMID: 20368438

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Project description:BackgroundSolid tumor hypoxic conditions prevent the generation of reactive oxygen species (ROS) and the formation of DNA double-strand breaks (DSBs) induced by ionizing radiation, which ultimately contributes to radiotherapy (RT) resistance. Recently, there have been significant technical advances in nanomedicine to reduce hypoxia by facilitating in situ O2 production, which in turn serves as a "radiosensitizer" to increase the sensitivity of tumor cells to ionizing radiation. However, off-target damage to the tumor-surrounding healthy tissue by high-energy radiation is often unavoidable, and tumor cells that are further away from the focal point of ionizing radiation may avoid damage. Therefore, there is an urgent need to develop an intelligent targeted nanoplatform to enable precise enhanced RT-induced DNA damage and combined therapy.ResultsHuman epidermal growth factor receptor 2 (Her2)-specific dimeric affibody (ZHer2) mediated cisplatin-loaded mesoporous polydopamine/MnO2/polydopamine nanoparticles (Pt@mPDA/MnO2/PDA-ZHer2 NPs) for MRI and enhanced chemo-radiotherapy of Her2-positive ovarian tumors is reported. These NPs are biodegradable under a simulated tumor microenvironment, resulting in accelerated cisplatin release, as well as localized production of O2. ZHer2, produced using the E. coli expression system, endowed NPs with Her2-dependent binding ability in Her2-positive SKOV-3 cells. An in vivo MRI revealed obvious T1 contrast enhancement at the tumor site. Moreover, these NPs achieved efficient tumor homing and penetration via the efficient internalization and penetrability of ZHer2. These NPs exhibited excellent inhibition of tumor growth with X-ray irradiation. An immunofluorescence assay showed that these NPs significantly reduced the expression of HIF-1α and improved ROS levels, resulting in radiosensitization.ConclusionsThe nanocarriers described in the present study integrated Her2 targeting, diagnosis and RT sensitization into a single platform, thus providing a novel approach for translational tumor theranostics.

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Metallofullerene nanoparticles circumvent tumor resistance to cisplatin by reactivating endocytosis.

Publications

Metallofullerene nanoparticles circumvent tumor resistance to cisplatin by reactivating endocytosis.

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