Prodrug Strategy to Achieve Lyophilizable, High Drug Loading Micelle Formulations Through Diester Derivatives of β‐Lapachone

Ma, Xinpeng; Huang, Xiumei; Huang, Gang; Li, Long Shan; Wang, Yiguang; Luo, Xuelian; Boothman, David A.; Gao, Jinming

doi:10.1002/adhm.201300590

Cited by 28 publications

(15 citation statements)

References 27 publications

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“…Diester derivatives of β-lap were synthesized with varying alkyl chain lengths as reported [25]. The dC 2 prodrug was still easily crystallized from micelles in aqueous solution and was not used in this study.…”

Section: Resultsmentioning

confidence: 99%

“…We chose dC 3 and dC 6 for further development to investigate the effect of chain length on micelle formulation and antitumor efficacy. The dC 3 M and dC 6 M nanoparticles were formed by a film hydration method [25] using a biocompatible and biodegradable PEG- b -PLA polymer at a theoretical loading density of 10 wt.%. Experimental loading contents were 9.7 ± 0.4 and 10.0 ± 0.3 wt.% for dC 3 and dC 6 prodrugs, respectively, demonstrating high drug loading efficiency (>95%, Fig.…”

Section: Resultsmentioning

confidence: 99%

“…β-Lap prodrugs and poly(ethylene glycol)-block-poly( d , l -lactic acid) (PEG- b -PLA) block copolymer (M n = 10 kD, the PEG and PLA segments were 5 kD) were synthesized following previously reported procedures [25,27]. Briefly for dC 3 , β-Lap (242 mg, 1 mmol), zinc powder (320 mg, 4.9 mmol), 40 mg sodium acetate (0.49 mmol), and 1 mL anhydrous propionic anhydride were mixed and stirred at 110 °C for 1 h. After reaction, the mixture was cooled to room temperature, filtered, and washed with 10 mL ethyl acetate.…”

Section: Methodsmentioning

confidence: 99%

“…β-Lap prodrug (dC 3 and dC 6 ) micelles were prepared by a film hydration method following a published protocol [25]. Briefly, dC 3 or dC 6 (10 mg) and PEG- b -PLA (90 mg) were first dissolved in acetonitrile (1 mL) and the solvent evaporated in vacuum using a rotary evaporator to form a solid thin film.…”

Section: Methodsmentioning

confidence: 99%

“…We demonstrate that dC 3 and dC 6 micelles (dC 3 M and dC 6 M, respectively) have greatly improved drug loading content (∼10%) and efficiency (>95%) in PEG- b -PLA micelles. This strategy allows easy scale-up formulations with high apparent drug solubility (>7 mg/mL), physical stability, and the ability for reconstitution after lyophilization [25]. …”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Esterase-activatable β-lapachone prodrug micelles for NQO1-targeted lung cancer therapy

Huang

Moore

et al. 2015

Journal of Controlled Release

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Lung cancer is one of the most lethal forms of cancer and current chemotherapeutic strategies lack broad specificity and efficacy. Recently, β-lapachone (β-lap) was shown to be highly efficacious in killing non-small cell lung cancer (NSCLC) cells regardless of their p53, cell cycle and caspase status. Pre-clinical and clinical use of β-lap (clinical form, ARQ501 or 761) is hampered by poor pharmacokinetics and toxicity due to hemolytic anemia. Here, we report the development and preclinical evaluation of β-lap prodrug nanotherapeutics consisting of diester derivatives of β-lap encapsulated in biocompatible and biodegradable poly(ethylene glycol)-b-poly(d,l-lactic acid) (PEG-b-PLA) micelles. Compared to the parent drug, diester derivatives of β-lap showed higher drug loading densities inside PEG-b-PLA micelles. After esterase treatment, micelle-delivered β-lap-dC3 and -dC6 prodrugs were converted to β-lap. Cytotoxicity assays using A549 and H596 lung cancer cells showed that both micelle formulations maintained NAD(P)H:quinone oxidoreductase 1 (NQO1)-dependent cytotoxicity. However, antitumor efficacy study of β-lap-dC3 micelles against orthotopic A549 NSCLC xenograft-bearing mice showed significantly greater long-term survival over β-lap-dC6 micelles or β-lap-HPβCD complexes. Improved therapeutic efficacy of β-lap-dC3 micelles correlated with higher area under the concentration-time curves of β-lap in tumors, and enhanced pharmacodynamic endpoints (e.g., PARP1 hyperactivation, γH2AX, and ATP depletion). β-Lap-dC3 prodrug micelles provide a promising strategy for NQO1-targeted therapy of lung cancer with improved safety and antitumor efficacy.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Esterase-activatable β-lapachone prodrug micelles for NQO1-targeted lung cancer therapy

Huang

Moore

et al. 2015

Journal of Controlled Release

Self Cite

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Tumor Microenvironment Triggered Cascade‐Activation Nanoplatform for Synergistic and Precise Treatment of Hepatocellular Carcinoma

Xin

Cai

et al. 2021

Adv Healthcare Materials

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Hepatocellular carcinoma (HCC) is one of the most common and deadliest malignancy cancers, which remains a major global health problem. At present, over 50% of patients with HCC have implemented systemic therapies, such as interventional therapy or local chemotherapy that are scarcely effective and induce serious side effects to the remaining normal liver, further limiting their clinical outcomes. Herein, a tumor microenvironment triggered cascade-activation nanoplatform (A-NP Lap/TPZ ) is prepared based on -lapachone ( -Lap) and tirapazamine (TPZ) for the synergistic therapy of HCC. The A-NP Lap/TPZ exerts its targeting effect by binding to the receptor of tumor cells with an external aptamer. In the tumor microenvironment, the nanoplatform can realize H 2 O 2 -triggered disassembly to release -Lap and TPZ. The released -Lap generates ROS to induce tumor cell apoptosis under the catalysis of the tumor cell over-expressed NAD(P)H-quinone oxidoreductase-1 (NQO1) enzyme. In this process, oxygen is consumed to intensify tumor hypoxia, and eventually cascade activates TPZ to exert the anti-tumor effect. The studies in vitro and in vivo consistently demonstrate that the as-prepared A-NP Lap/TPZ nanoplatform possesses an excellent synergistic anti-tumor effect. This design of nanoplatform with cascade activation effect provides a promising strategy for HCC treatment.

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Tailored Beta‐Lapachone Nanomedicines for Cancer‐Specific Therapy

Feng

Guo

Wang

et al. 2023

Adv Healthcare Materials

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Nanotechnology shows the power to improve efficacy and reduce the adverse effects of anticancer agents. As a quinone‐containing compound, beta‐lapachone (LAP) is widely employed for targeted anticancer therapy under hypoxia. The principal mechanism of LAP‐mediated cytotoxicity is believed due to the continuous generation of reactive oxygen species with the aid of NAD(P)H: quinone oxidoreductase 1 (NQO1). The cancer selectivity of LAP relies on the difference between NQO1 expression in tumors and that in healthy organs. Despite this, the clinical translation of LAP faces the problem of narrow therapeutic window that is challenging for dose regimen design. Herein, the multifaceted anticancer mechanism of LAP is briefly introduced, the advance of nanocarriers for LAP delivery is reviewed, and the combinational delivery approaches to enhance LAP potency in recent years are summarized. The mechanisms by which nanosystems boost LAP efficacy, including tumor targeting, cellular uptake enhancement, controlled cargo release, enhanced Fenton or Fenton‐like reaction, and multidrug synergism, are also presented. The problems of LAP anticancer nanomedicines and the prospective solutions are discussed. The current review may help to unlock the potential of cancer‐specific LAP therapy and speed up its clinical translation.

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Prodrug Strategy to Achieve Lyophilizable, High Drug Loading Micelle Formulations Through Diester Derivatives of β‐Lapachone

Cited by 28 publications

References 27 publications

Esterase-activatable β-lapachone prodrug micelles for NQO1-targeted lung cancer therapy

Esterase-activatable β-lapachone prodrug micelles for NQO1-targeted lung cancer therapy

Tumor Microenvironment Triggered Cascade‐Activation Nanoplatform for Synergistic and Precise Treatment of Hepatocellular Carcinoma

Tailored Beta‐Lapachone Nanomedicines for Cancer‐Specific Therapy

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