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Clathrin light chain-conjugated drug delivery for cancer.

ABSTRACT: Targeted drug delivery systems hold the remarkable potential to improve the therapeutic index of anticancer medications markedly. Here, we report a targeted delivery platform for cancer treatment using clathrin light chain (CLC)-conjugated drugs. We conjugated CLC to paclitaxel (PTX) through a glutaric anhydride at high efficiency. Labeled CLCs localized to 4T1 tumors implanted in mice, and conjugation of PTX to CLC enhanced its delivery to these tumors. Treatment of three different mouse models of cancer-melanoma, breast cancer, and lung cancer-with CLC-PTX resulted in significant growth inhibition of both the primary tumor and metastatic lesions, as compared to treatment with free PTX. CLC-PTX treatment caused a marked increase in apoptosis of tumor cells and reduction of tumor angiogenesis. Our data suggested HSP70 as a binding partner for CLC. Our study demonstrates that CLC-based drug-conjugates constitute a novel drug delivery platform that can augment the effects of chemotherapeutics in treating a variety of cancers. Moreover, conjugation of therapeutics with CLC may be used as means by which drugs are delivered specifically to primary tumors and metastatic lesions, thereby prolonging the survival of cancer patients.

SUBMITTER: Jung S

PROVIDER: S-EPMC9842032 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Clathrin light chain-conjugated drug delivery for cancer.

Jung Sungwook S Jiang Liwei L Zhao Jing J Shultz Leonard D LD Greiner Dale L DL Bae Munhyung M Li Xiaofei X Ordikhani Farideh F Kuai Rui R Joseph John J Kasinath Vivek V Elmaleh David R DR Abdi Reza R

Bioengineering & translational medicine 20221128 1

Targeted drug delivery systems hold the remarkable potential to improve the therapeutic index of anticancer medications markedly. Here, we report a targeted delivery platform for cancer treatment using clathrin light chain (CLC)-conjugated drugs. We conjugated CLC to paclitaxel (PTX) through a glutaric anhydride at high efficiency. Labeled CLCs localized to 4T1 tumors implanted in mice, and conjugation of PTX to CLC enhanced its delivery to these tumors. Treatment of three different mouse models ...[more]

PMID: 36684105

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Project description:To overcome the limitation of conventional nanodrugs in tumor targeting efficiency, coupling targeting ligands to polymeric nanoparticles can enhance the specific binding of nanodrugs to tumors. Cyclo(Arg-Gly-Asp-d-Phe-Lys) (abbreviated as c(RGDfK)) peptide has been widely adopted due to its high affinity to the tumor marker αvβ3 integrin receptor. In this study, we develop a cRGD peptide-conjugated camptothecin (CPT) prodrug, which enables self-assembly of nanoparticles for precise targeting and enrichment in tumor tissue. We first synthesized a camptothecin derivative (CPT-ss-N3) with a reduction-sensitive bond and simultaneously modified PEG to obtain cRGD-PEG-N3. After ring-opening polymerization of the 2-(but-3-yn-1-yolxy)-2-oxo-1,3,2-dioxaphospholane (BYP), an amphiphilic polymeric prodrug, referred to as cRGD-PEG-g-(PBYP-ss-CPT), was obtained via copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. The self-assembly in buffer solution of the cRGD-functional prodrug was studied through DLS and TEM. The in vitro drug release behavior of cRGD-PEG-g-(PBYP-ss-CPT) nanoparticles was investigated. The results show that the nanoparticles are reduction-responsive and the bonded CPT can be released. Endocytosis and MTT assays demonstrate that the cRGD-conjugated prodrug has better affinity for tumor cells, accumulates more intracellularly, and is therefore, more effective. The in vivo drug metabolism studies show that nanoparticles greatly prolong the retention time in circulation. By monitoring drug distribution in tumor and in various tissues, we find that free CPT can be rapidly metabolized, resulting in low accumulation in all tissues. However, cRGD-PEG-g-(PBYP-ss-CPT) nanoparticles accumulate in tumor tissues in higher amounts than PEG-g-(PBYP-ss-CPT) nanoparticles, except for the inevitable capture by the liver. This indicates that the nanomedicine with cRGD has a certain targeting property, which can improve drug delivery efficiency.

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Clathrin light chain-conjugated drug delivery for cancer.

Publications

Clathrin light chain-conjugated drug delivery for cancer.

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