Design and development of multifunctional polyphosphoester-based nanoparticles for ultrahigh paclitaxel dual loading

Zhang, Fuwu; Khan, Sarosh; Li, Richen; Smolen, Justin A.; Zhang, Shiyi; Zhu, Guizhi; Jahnke, Ashlee A.; Elsabahy, Mahmoud; Chen, Xiaoyuan; Wooley, Karen L.

doi:10.1039/c7nr05935c

Cited by 26 publications

(13 citation statements)

References 23 publications

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“…Recently, several nanodrug formulations have been developed to solve these problems. − For example, Cheng and co-workers reported about nanoparticles that could load the dimerized drug with over 50% drug loading content and nearly 100% drug loading efficiency . This nanoformulation showed excellent stability under physiological conditions without triggering, while thiol triggering resulted in a controlled release of its authentic form of drug.…”

Section: Introductionmentioning

confidence: 99%

Development of Zwitterionic Polypeptide Nanoformulation with High Doxorubicin Loading Content for Targeted Drug Delivery

Lin

Yuan

et al. 2018

Langmuir

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Much attention has been drawn to targeted nanodrug delivery systems due to their high therapeutic efficacy in cancer treatment. In this work, doxorubicin (DOX) was incorporated into a zwitterionic arginyl-glycyl-aspartic acid (RGD)-conjugated polypeptide by an emulsion solvent evaporation technique with high drug loading content (45%) and high drug loading efficiency (95%). This zwitterionic nanoformulation showed excellent colloidal stability at high dilution and in serum. The pH-induced disintegration and enzyme-induced degradation of the nanoformulation were confirmed by dynamic light scattering and gel permeation chromatography. Efficient internalization of DOX in the cells and high antitumor activity in vitro was observed. Compared with the free drug, this nanoformulation showed higher accumulation in tumor and lower systemic toxicity in vivo. The DOX-loaded zwitterionic RGD-conjugated polypeptide vesicles show potential application for targeted drug delivery in the clinic.

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Section: Introductionmentioning

confidence: 99%

Development of Zwitterionic Polypeptide Nanoformulation with High Doxorubicin Loading Content for Targeted Drug Delivery

Lin

Yuan

et al. 2018

Langmuir

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“…The development of many pharmacologically active compounds has been hindered by poor pharmacokinetics, low solubility, and formulation difficulties. For instance, PTX, one of the most widely used and effective antitumor agents derived from natural sources for a wide spectrum of tumors is highly lipophilic with very poor pharmacokinetics 26 , 27 . Abraxane®, a PTX albumin-bound nanoparticle delivery system with particle diameters of ~130 nm, was approved by the US FDA for the treatment of metastatic breast cancer.…”

Section: Introductionmentioning

confidence: 99%

A paclitaxel prodrug with bifunctional folate and albumin binding moieties for both passive and active targeted cancer therapy

Shan¹,

Xin²,

Zhang³

et al. 2018

Theranostics

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Folate receptor (FR) has proven to be a valuable target for chemotherapy using folic acid (FA) conjugates. However, FA-conjugated chemotherapeutics still have low therapeutic efficacy accompanied with side effects, resulting from complications such as short circulation half-life, limited tumor delivery, as well as high kidney accumulation. Herein, we present a novel FA-conjugated paclitaxel (PTX) prodrug which was additionally conjugated with an Evans blue (EB) derivative for albumin binding. The resulting bifunctional prodrug prolonged blood circulation, enhanced tumor accumulation, and consequently improved tumor therapeutic efficacy.Methods: Fmoc-Cys(Trt)-OH was coupled onto PTX at the 7'-OH position for further synthesis of ester prodrug FA-PTX-EB. The targeting ability was investigated using confocal microscopy and flow cytometry. The pharmacokinetics of this bifunctional compound was also studied. Meanwhile, cell viability was evaluated in normal cells and three cancer cell lines by MTT assay. In vivo therapeutic effect was tested on FR-α overexpressing MDA-MB-231 tumor model.Results: Compared with free PTX, the FA-PTX, PTX-EB and FA-PTX-EB prodrugs increased circulation half-life in mice from 2.19 to 3.82, 4.41, and 7.51 h, respectively. Pharmacokinetics studies showed that the FA-PTX-EB delivered more PTX to tumors than FA-PTX and free PTX. In vitro and in vivo studies demonstrated that FA-EB-conjugated PTX induced potent antitumor activity.Conclusion: FA-PTX-EB showed prolonged blood circulation, enhanced drug accumulation in tumors, higher therapeutic index, and lower side effects than either free PTX or monofunctional FA-PTX and EB-PTX. The results support the potential of using EB for the development of long-acting therapeutics.

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“…Nanoparticles derived from biodegradable polymers, such as polyesters, 15 polypeptides, 16 PPEs, 14,17,18 and polycarbonates, 19,20 have gained increasing interest for nanomedicines, which reduce the potential for long-term accumulation and associated adverse effects. Recently, our group employed functional glucose-derived polycarbonates (PGCs) to construct nanostructures with tunable sizes, surface charges, and morphologies that are, notably, capable of degradation into natural products, for example, glucose, carbon dioxide, and ethanol.…”

Section: ■ Introductionmentioning

confidence: 99%

Chemical Design of Both a Glutathione-Sensitive Dimeric Drug Guest and a Glucose-Derived Nanocarrier Host to Achieve Enhanced Osteosarcoma Lung Metastatic Anticancer Selectivity

Khan

Clanton

et al. 2018

J. Am. Chem. Soc.

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Although nanomedicines have been pursued for nearly 20 years, fundamental chemical strategies that seek to optimize both the drug and drug carrier together in a concerted effort remain uncommon yet may be powerful. In this work, two block polymers and one dimeric prodrug molecule were designed to be coassembled into degradable, functional nanocarriers, where the chemistry of each component was defined to accomplish important tasks. The result is a poly(ethylene glycol) (PEG)-protected redox-responsive dimeric paclitaxel (diPTX)-loaded cationic poly(d-glucose carbonate) micelle (diPTX@CPGC). These nanostructures showed tunable sizes and surface charges and displayed controlled PTX drug release profiles in the presence of reducing agents, such as glutathione (GSH) and dithiothreitol (DTT), thereby resulting in significant selectivity for killing cancer cells over healthy cells. Compared to free PTX and diPTX, diPTX@CPGC exhibited improved tumor penetration and significant inhibition of tumor cell growth toward osteosarcoma (OS) lung metastases with minimal side effects both in vitro and in vivo, indicating the promise of diPTX@CPGC as optimized anticancer therapeutic agents for treatment of OS lung metastases.

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Design and development of multifunctional polyphosphoester-based nanoparticles for ultrahigh paclitaxel dual loading

Cited by 26 publications

References 23 publications

Development of Zwitterionic Polypeptide Nanoformulation with High Doxorubicin Loading Content for Targeted Drug Delivery

Development of Zwitterionic Polypeptide Nanoformulation with High Doxorubicin Loading Content for Targeted Drug Delivery

A paclitaxel prodrug with bifunctional folate and albumin binding moieties for both passive and active targeted cancer therapy

Chemical Design of Both a Glutathione-Sensitive Dimeric Drug Guest and a Glucose-Derived Nanocarrier Host to Achieve Enhanced Osteosarcoma Lung Metastatic Anticancer Selectivity

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