Cathepsin B-Overexpressed Tumor Cell Activatable Albumin-Binding Doxorubicin Prodrug for Cancer-Targeted Therapy.
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ABSTRACT:
SUBMITTER: Cho H
PROVIDER: S-EPMC8780658 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Lung cancer is one of the most lethal forms of cancer and current chemotherapeutic strategies lack broad specificity and efficacy. Recently, ?-lapachone (?-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 ?-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 ?-lap prodrug nanotherapeutics consisting of diester derivatives of ?-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 ?-lap showed higher drug loading densities inside PEG-b-PLA micelles. After esterase treatment, micelle-delivered ?-lap-dC3 and -dC6 prodrugs were converted to ?-lap. Cytotoxicity assays using A549 and H596 lung cancer cells showed that both micelle formulations maintainedquinone oxidoreductase 1 (NQO1)-dependent cytotoxicity. However, antitumor efficacy study of ?-lap-dC3 micelles against orthotopic A549 NSCLC xenograft-bearing mice showed significantly greater long-term survival over ?-lap-dC6 micelles or ?-lap-HP?CD complexes. Improved therapeutic efficacy of ?-lap-dC3 micelles correlated with higher area under the concentration-time curves of ?-lap in tumors, and enhanced pharmacodynamic endpoints (e.g., PARP1 hyperactivation, ?H2AX, and ATP depletion). ?-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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Project description:Human serum albumin (HSA) improves the pharmacokinetic profile of drugs attached to it, making it an attractive carrier with proven clinical success. In our previous studies, we have shown that Caveolin-1 (Cav-1) and caveolae-mediated endocytosis play important roles in the uptake of HSA and albumin-bound drugs. Doxorubicin is an FDA-approved chemotherapeutic agent that is effective against multiple cancers, but its clinical applicability has been hampered by its high toxicity levels. In this study, a doxorubicin-prodrug was developed that could independently and avidly bind HSA in circulation, called IPBA-Dox. We first developed and characterized IPBA-Dox and confirmed that it can bind albumin in vitro while retaining a potent cytotoxic effect. We then verified that it efficiently binds to HSA in circulation, leading to an improvement in the pharmacokinetic profile of the drug. In addition, we tested our prodrug for Cav-1 selectivity and found that it preferentially affects cells that express relatively higher levels of Cav-1 in vitro and in vivo. Moreover, we found that our compound was well tolerated in vivo at concentrations at which doxorubicin was lethal. Altogether, we have developed a doxorubicin-prodrug that can successfully bind HSA, retaining a strong cytotoxic effect that preferentially targets Cav-1 positive cells while improving the general tolerability of the drug.
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Project description:As an effective drug delivery strategy for traditional antitumor drugs, the stimulus-responsive albumin-based prodrugs are getting more and more attention. These prodrugs only release drugs in specific tumor microenvironments, which can prevent premature release of the drug in the circulation. Tumor hypoxia is a fundamental feature of the solid tumor microenvironment. As a hypoxia-activated linker, the 5-position branched linker of 1-methyl-2-nitro-5-hydroxymethylimidazole can be a trigger for albumin-based prodrugs. In this study, we report the synthesis and biological evaluation of the hypoxia-activated albumin-binding prodrug Mal-azo-Exatecan. After intravenous administration, the maleimide on the side chain can rapidly bind to endogenous albumin, enabling the prodrugs to accumulate in tumors, where tumor-associated hypoxia microenvironments trigger the selective release of Exatecan. The 5-position branched linker of 1-methyl-2-nitro-5-hydroxymethylimidazole as a cleavable linker has high plasma stability and does not cause Exatecan release from HSA-azo-Exatecan during circulation in vivo, avoiding systemic side effects caused by Exatecan.
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Project description:Herein we describe the design and synthesis of a folate-doxorubicin conjugate with activatable fluorescence and activatable cytotoxicity. In this study we discovered that the cytotoxicity and fluorescence of doxorubicin are quenched (OFF) when covalently linked with folic acid. Most importantly, when the conjugate is designed with a disulfide bond linking the targeting folate unit and the cytotoxic doxorubicin, a targeted activatable prodrug is obtained that becomes activated (ON) within the cell by glutathione-mediated dissociation and nuclear translocation, showing enhanced fluorescence and cellular toxicity. In our novel design, folic acid acted as both a targeting ligand for the folate receptor as well as a quencher for doxorubicin's fluorescence.
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Project description: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-? 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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Project description:In this study, we investigated the potential of a dual-targeted pH-sensitive doxorubicin prodrug-microbubble complex (DPMC) in ultrasound (US)-assisted antitumor therapy. The doxorubicin prodrug (DP) consists of a succinylated-heparin carrier conjugated with doxorubicin (DOX) via hydrazone linkage and decorated with dual targeting ligands, folate and cRGD peptide. Combination of microbubble (MB) and DP, generated via avidin-biotin binding, promoted intracellular accumulation and improved therapeutic efficiency assisted by US cavitation and sonoporation. Aggregates of prepared DP were observed with an inhomogeneous size distribution (average diameters: 149.6±29.8 nm and 1036.2±38.8 nm, PDI: 1.0) while DPMC exhibited a uniform distribution (average diameter: 5.804±2.1 μm), facilitating its usage for drug delivery. Notably, upon US exposure, DPMC was disrupted and aggregated DP dispersed into homogeneous small-sized nanoparticles (average diameter: 128.6±42.3 nm, PDI: 0.21). DPMC could target to angiogenic endothelial cells in tumor region via αvβ3-mediated recognition and subsequently facilitate its specific binding to tumor cells mediated via recognition of folate receptor (FR) after US exposure. In vitro experiments showed higher tumor specificity and killing ability of DPMC with US than free DOX and DP for breast cancer MCF-7 cells. Furthermore, significant accumulation and specificity for tumor tissues of DPMC with US were detected using in vivo fluorescence and ultrasound molecular imaging, indicating its potential to integrate tumor imaging and therapy. In particular, through inducing apoptosis, inhibiting cell proliferation and antagonizing angiogenesis, DPMC with US produced higher tumor inhibition rates than DOX or DPMC without US in MCF-7 xenograft tumor-bearing mice while inducing no obvious body weight loss. Our strategy provides an effective platform for the delivery of large-sized or aggregated particles to tumor sites, thereby extending their therapeutic applications in vivo.
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Project description:We have developed a novel albumin-binding prodrug of doxorubicin that incorporates p-aminobenzyloxycarbonyl (PABC) as a 1,6 self-immolative spacer in addition to the heptapeptide, Arg-Ser-Ser-Tyr-Tyr-Ser-Leu, as a substrate for the prostate-specific antigen (PSA) that is overexpressed in prostate carcinoma and represents a molecular target for selectively releasing an anticancer agent from a prodrug formulation. The prodrug exhibited good water solubility and was bound rapidly to the cysteine-34 position of human serum albumin. Incubation studies with PSA demonstrated that the albumin-bound form of the prodrug was cleaved rapidly at the P1-P1' scissile bond, releasing H-Ser-Leu-PABC-DOXO, which was further degraded to release doxorubicin as a final cleavage product within a few hours in prostate tumor tissue homogenates as well as in PSA-positive LNCaP LN cell lysates. Moreover, our prodrug exhibited antiproliferative activity in a low micromolar range against a PSA-expressing prostate cancer cell line (LNCaP).
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Project description:Rationale: Chemodynamic therapy (CDT) is an emerging tumor-specific therapeutic strategy. However, the anticancer activity of CDT is impeded by the insufficient Fenton catalytic efficiency and the high concentration of glutathione (GSH) in the tumor cells. Also, it is challenging to eliminate tumors with CDT alone. Thus, simple strategies aimed at constructing well-designed nanomedicines that can improve therapeutic efficiency of CDT and simultaneously incorporate extra therapeutic modes as helper are meaningful and highly required. Method: Tailored to specific features of tumor microenvironment (TME), in this study, we developed a biosafe, stable and TME-activated theranostic nanoplatform (P(HSD-Cu-DA)) for photoacoustic imaging (PAI) and self-amplified cooperative therapy. This intelligent nanoplatform was fabricated following a simple one-pot coordination and polymerization strategy by using dopamine and Cu2+ as precursors and redox-responsive hydroxyethyl starch prodrugs (HES-SS-DOX) as stabilizer. Results: Interestingly, the pre-doped Cu2+ in polydopamine (PDA) framework can endow P(HSD-Cu-DA) NPs with tumor-specific CDT ability and remarkably enhance NIR absorption of PDA. PAI and biodistribution tests proved such nanoplatform can effectively accumulate in tumor tissues. Following enrichment, massive amounts of toxic hydroxyl radicals (·OH, for CDT) and free DOX (for chemotherapy) were generated by the stimulation of TME, which was further boosted by local hyperthermia. Concomitantly, in the process of activating these therapeutic functions, GSH depletion triggered by disulfide bond (-SS-) breakage and Cu2+ reduction within tumor cells occurred, further amplifying intratumoral oxidative stress. Importantly, the framework structure dominated by bioinspired polydopamine and clinical-used HES guaranteed the long-term biosafety of in vivo treatment. As a result, the mutual promotion among different components yields a potent tumor suppression outcome and minimized systemic toxicity, with one dosage of drug administration and laser irradiation, respectively. Conclusion: This work provides novel insights into designing efficient and tumor-specific activatable nanotherapeutics with significant clinical translational potential for cancer therapy.
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Project description:The design of targeted platinum(iv) prodrugs is a very promising approach to enhance the low selectivity of platinum(ii) drugs towards cancerous tissue in order to reduce the impact on healthy tissue and, consequently, the often severe side-effects. Herein, we report a set of mono-functionalized cis- and oxaliplatin-based platinum(iv) complexes bearing a maleimide moiety, which allows selective binding to serum albumin in the bloodstream. This leads not only to a prolonged plasma half-life by avoidance of fast renal clearance, but also to preferential accumulation of the drug in the tumor tissue due to the EPR-effect. Additionally, analogous succinimide-functionalized derivatives were prepared to verify the influence of the maleimide moiety. First experiments showed that all the maleimide compounds are stable and also possess good albumin-binding properties in whole serum. Further analytical studies on in vivo samples proved the highly increased plasma half-life, as well as tumor accumulation of the maleimide-functionalized substances. In vivo antitumor experiments with CT-26-bearing mice showed that, in contrast to the cisplatin derivatives, the oxaliplatin-based complexes had exceptionally better activity than the free drug resulting in the cure of the majority of treated mice. Subsequent analysis suggested that a distinctly faster reduction as well as reduced tumor accumulation of the cisplatin derivative might explain the worse performance compared to the oxaliplatin(iv) complexes. Taken together, a novel lead platinum(iv) complex with outstanding antitumor activity is presented, which will now be further developed towards clinical phase I trials.
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