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Continuous Spatiotemporal Therapy of A Full-API Nanodrug via Multi-Step Tandem Endogenous Biosynthesis

Fang, Fang, Wang, Sa, Song, Yueyue, Sun, Meng, Chen, Wen-Cheng, Zhao, Dongxu, Zhang, Jinfeng·2023·Nature Communications
DOI 10.1038/s41467-023-37315-0PMC PMC10039359
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Abstract

Nanomedicine holds great promise to enhance cancer therapy. However, low active pharmaceutical ingredient (API) loading content, unpredictable drug release, and potential toxicity from excipients limit their translational capability. We herein report a full-API nanodrug composed of FDA-approved 5-aminolevulinic acid (ALA), human essential element Fe 3+ , and natural bioactive compound curcumin with an ideal API content and pH-responsive release profile for continuous spatiotemporal cancer therapy achieved by multi-step tandem endogenous biosynthesis. First, ALA enzymatically converts into photosensitizer protoporphyrin IX (PpIX). Afterward, multiple downstream products including carbon monoxide (CO), Fe 2+ , biliverdin (BV), and bilirubin (BR) are individually biosynthesized through the PpIX-heme-CO/Fe 2+ /BV-BR metabolic pathway, further cooperating with released Fe 3+ and curcumin, ultimately eliciting mitochondria damage, membrane disruption, and intracytoplasmic injury. This work not only provides a paradigm for exploiting diversified metabolites for tumor suppression, but also presents a safe and efficient full-API nanodrug, facilitating the practical translation of nanodrugs.

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Fig. 1 Schematic illustration of multi-step tandem endogenous biosynthesis triggered by the AFeC FANDs for continuous spatiotemporal cancer therapy. First, the Full-API nanodrugs consisted of FDA-approved ALA and Cur, as well as human essential Fe3+ were fabricated by the metal coordination-driven self-assembly, which could accumulate at tumor sites via the enhanced permeability and retention (EPR) effect, and release active ingredients in acid tumor cells. Importantly, the released ALA could endogenously biosynthesize multiple metabolic products including PpIX, carbon monoxide (CO), Fe2+, biliverdin (BV), and bilirubin (BR), which further synergized with the released Fe3+ and curcumin (Cur), ultimately inducing mitochondria damage, membrane disruption, and intracytoplasmic injury.
Fig. 1 Schematic illustration of multi-step tandem endogenous biosynthesis triggered by the AFeC FANDs for continuous spatiotemporal cancer therapy. First, the Full-API nanodrugs consisted of FDA-approved ALA and Cur, as well as human essential Fe3+ were fabricated by the metal coordination-driven self-assembly, which could accumulate at tumor sites via the enhanced permeability and retention (EPR) effect, and release active ingredients in acid tumor cells. Importantly, the released ALA could endogenously biosynthesize multiple metabolic products including PpIX, carbon monoxide (CO), Fe2+, biliverdin (BV), and bilirubin (BR), which further synergized with the released Fe3+ and curcumin (Cur), ultimately inducing mitochondria damage, membrane disruption, and intracytoplasmic injury.CC BY · PubMed Central
Fig. 2 Preparation and characterization of the AFeC FANDs. a SEM and b TEM images of the AFeC FANDs. c Size distribution of the AFeC FANDs. d Zeta potential of the AFeC FANDs, inset is their Tyndall effect exhibition. e Element mapping for Fe, C, and N of the AFeC FANDs. f UV-vis absorption (Abs) and g fluorescence (FL) spectra of the free FeCl3, 5-aminolevulinic acid (ALA), curcumin (Cur), and AFeC FANDs. h In vitro release of Cur from the AFeC FANDs in the buffer solutions of pH 5.0, 6.0 and 7.4. i–k TEM images of the AFeC FANDs incubated in pH 5.0, 6.0 and 7.4 buffer solutions for 6 h. The results in (a, b, e, i–k) were representative of three independent experiments. Data in (h) were presented as mean ± SD, n = 3 independent samples. P value was calculated by two-tailed unpaired t-test. Source data were provided in the Source Data file.
Fig. 2 Preparation and characterization of the AFeC FANDs. a SEM and b TEM images of the AFeC FANDs. c Size distribution of the AFeC FANDs. d Zeta potential of the AFeC FANDs, inset is their Tyndall effect exhibition. e Element mapping for Fe, C, and N of the AFeC FANDs. f UV-vis absorption (Abs) and g fluorescence (FL) spectra of the free FeCl3, 5-aminolevulinic acid (ALA), curcumin (Cur), and AFeC FANDs. h In vitro release of Cur from the AFeC FANDs in the buffer solutions of pH 5.0, 6.0 and 7.4. i–k TEM images of the AFeC FANDs incubated in pH 5.0, 6.0 and 7.4 buffer solutions for 6 h. The results in (a, b, e, i–k) were representative of three independent experiments. Data in (h) were presented as mean ± SD, n = 3 independent samples. P value was calculated by two-tailed unpaired t-test. Source data were provided in the Source Data file.CC BY · PubMed Central
Fig. 3 Formation mechanisms of the AFeC FANDs. a Molecular cluster changes of 5-aminolevulinic acid (ALA), FeCl3, and curcumin (Cur) during 100 ns simulation (blue balls: carbon; deep blue balls: nitrogen; red balls: oxygen; white balls: hydrogen; brown balls: Fe3+). b Intermolecular interactions analysis in the AFeC FANDs. c Evolution of aggregates without or with ALA simulated by molecular dynamics (brown: Fe3+; yellow: Cur; blue: ALA). d–f TEM images of the FeC FANDs, ALA and FeCl3 mixture, as well as ALA and Cur mixture. Scale bar: 200 nm. The changes in g UV-vis absorption and h fluorescence emission of the AFeC FANDs treated with water, THF, NaCl, Urea, sodium dodecyl sulfate (SDS), ethylenediaminetetraacetic acid (EDTA) (V/V = 1:1). i XRD pattern of the AFeC FANDs. The results in (d–f) were representative of three independent experiments. Source data were provided in the Source Data file.
Fig. 3 Formation mechanisms of the AFeC FANDs. a Molecular cluster changes of 5-aminolevulinic acid (ALA), FeCl3, and curcumin (Cur) during 100 ns simulation (blue balls: carbon; deep blue balls: nitrogen; red balls: oxygen; white balls: hydrogen; brown balls: Fe3+). b Intermolecular interactions analysis in the AFeC FANDs. c Evolution of aggregates without or with ALA simulated by molecular dynamics (brown: Fe3+; yellow: Cur; blue: ALA). d–f TEM images of the FeC FANDs, ALA and FeCl3 mixture, as well as ALA and Cur mixture. Scale bar: 200 nm. The changes in g UV-vis absorption and h fluorescence emission of the AFeC FANDs treated with water, THF, NaCl, Urea, sodium dodecyl sulfate (SDS), ethylenediaminetetraacetic acid (EDTA) (V/V = 1:1). i XRD pattern of the AFeC FANDs. The results in (d–f) were representative of three independent experiments. Source data were provided in the Source Data file.CC BY · PubMed Central
Fig. 4 Temporal endogenous biosynthesis of a series of therapeutic metabolites based on ALA-PpIX-heme-CO/Fe2+/BV-BR metabolism. a Simplified scheme of the tandem metabolism pathway of 5-aminolevulinic acid (ALA). b Fluorescence images and c the corresponding mean fluorescence intensity (MFI) quantifications of PpIX, CO, Fe2+, and biliverdin (BV) in A549 cells with various treatments. d Cellular quantitative analysis of endogenous bilirubin (BR) in different groups by ELISA kits. e Persistent generation of PpIX, CO, Fe2+, and BV in ALA or AFeC FANDs treated A549 cells with different incubation times (The full images of these insets were displayed in Supplementary Fig. 5). Data in (c–e) were presented as mean ± SD, n = 3 biologically independent samples. P values were calculated by two-tailed unpaired t-test. Source data were provided in the Source Data file.
Fig. 4 Temporal endogenous biosynthesis of a series of therapeutic metabolites based on ALA-PpIX-heme-CO/Fe2+/BV-BR metabolism. a Simplified scheme of the tandem metabolism pathway of 5-aminolevulinic acid (ALA). b Fluorescence images and c the corresponding mean fluorescence intensity (MFI) quantifications of PpIX, CO, Fe2+, and biliverdin (BV) in A549 cells with various treatments. d Cellular quantitative analysis of endogenous bilirubin (BR) in different groups by ELISA kits. e Persistent generation of PpIX, CO, Fe2+, and BV in ALA or AFeC FANDs treated A549 cells with different incubation times (The full images of these insets were displayed in Supplementary Fig. 5). Data in (c–e) were presented as mean ± SD, n = 3 biologically independent samples. P values were calculated by two-tailed unpaired t-test. Source data were provided in the Source Data file.CC BY · PubMed Central
Fig. 5 The evaluation of the multi-spatial and multi-model therapy of the AFeC FANDs in vitro. a Mechanisms of the AFeC FANDs-mediated continuous spatiotemporal cancer therapeutics. b Reactive oxygen species (ROS) generation analysis in A549 cells with different treatments (green: DCFH-DA labeled ROS). c Representative mitochondria (Mito) colocalization images of the protoporphyrin IX (PpIX) biosynthesized by AFeC FANDs (rp: Pearson’s colocalization coefficient). d Mitochondria damage in A549 cells with various treatments detected by JC-1 staining. e Absorbance at 509 nm of the complex of Fe2+ with 1,10-phenanthroline in different groups. Inset: the corresponding visual color changes. f Ferroptosis estimation at cellular levels (green: BODIPY 581/591 C11 labeled lipid peroxidation (LPO)). g Cell membrane colocalization assessment of the LPO produced by ferroptosis. h Photothermal heating curves of biliverdin (BV) solutions with different concentrations upon 635 nm laser (0.3 W cm−2) irradiation, and the corresponding infrared thermal images. i Subcellular localization of the curcumin (Cur) in A549 cells (blue: DAPI labeled nucleus, red: DiD labeled cell plasma membrane, green: Cur). j Transfection of the Ad-mCherry-GFP-LC3B into A549 cells and measurement of the autophagosomes by CLSM. k Cell viabilities of A549 cells with various administrations. l Apoptosis study of A549 cells with different treatments by flow cytometric analysis. The results in (b–d, f, g, i, j) were representative of three independent experiments. Data in (e, k) were presented as mean ± SD, n = 3 independent samples in (e), n = 5 biologically independent samples in (k). P values were calculated by two-tailed unpaired t-test. Source data were provided in the Source Data file.
Fig. 5 The evaluation of the multi-spatial and multi-model therapy of the AFeC FANDs in vitro. a Mechanisms of the AFeC FANDs-mediated continuous spatiotemporal cancer therapeutics. b Reactive oxygen species (ROS) generation analysis in A549 cells with different treatments (green: DCFH-DA labeled ROS). c Representative mitochondria (Mito) colocalization images of the protoporphyrin IX (PpIX) biosynthesized by AFeC FANDs (rp: Pearson’s colocalization coefficient). d Mitochondria damage in A549 cells with various treatments detected by JC-1 staining. e Absorbance at 509 nm of the complex of Fe2+ with 1,10-phenanthroline in different groups. Inset: the corresponding visual color changes. f Ferroptosis estimation at cellular levels (green: BODIPY 581/591 C11 labeled lipid peroxidation (LPO)). g Cell membrane colocalization assessment of the LPO produced by ferroptosis. h Photothermal heating curves of biliverdin (BV) solutions with different concentrations upon 635 nm laser (0.3 W cm−2) irradiation, and the corresponding infrared thermal images. i Subcellular localization of the curcumin (Cur) in A549 cells (blue: DAPI labeled nucleus, red: DiD labeled cell plasma membrane, green: Cur). j Transfection of the Ad-mCherry-GFP-LC3B into A549 cells and measurement of the autophagosomes by CLSM. k Cell viabilities of A549 cells with various administrations. l Apoptosis study of A549 cells with different treatments by flow cytometric analysis. The results in (b–d, f, g, i, j) were representative of three independent experiments. Data in (e, k) were presented as mean ± SD, n = 3 independent samples in (e), n = 5 biologically independent samples in (k). P values were calculated by two-tailed unpaired t-test. Source data were provided in the Source Data file.CC BY · PubMed Central
Fig. 6 In vivo antitumor activities of the AFeC FANDs. a Ex vivo fluorescence imaging of the tumor and major organs from mice after i.v. injection of the AFeC FANDs. b Treatment schedule for the anticancer efficiency and mechanism assessments of the as-prepared FANDs. c Infrared thermal images of the mice and d the corresponding temperature rises of tumors after treatment with PBS, 5-aminolevulinic acid (ALA), AFeC FANDs upon 635 nm laser at different time intervals. e Tumor volumes of mice with various treatments during 14 days. f Weights of the tumors extracted from mice in varied groups at the end of therapy. g Photographs of A549 tumor-bearing mice in different groups before and after 14 day-treatments. h Body weights of mice in various groups during 14 day-therapy. i Hematoxylin and eosin (H&E), reactive oxygen species (ROS), lipoxygenase enzyme (FACL4), and glutathione peroxidase 4 (GPX4) staining of tumors from mice in different groups. Scale bar: 50 μm. The results in (i) were representative of three independent mice. Data in (d–f, h) were presented as mean ± SD, n = 3 biologically independent mice in (d), n = 6 biologically independent mice in (e, f, h). P values were calculated by two-tailed unpaired t-test. Source data were provided in the Source Data file.
Fig. 6 In vivo antitumor activities of the AFeC FANDs. a Ex vivo fluorescence imaging of the tumor and major organs from mice after i.v. injection of the AFeC FANDs. b Treatment schedule for the anticancer efficiency and mechanism assessments of the as-prepared FANDs. c Infrared thermal images of the mice and d the corresponding temperature rises of tumors after treatment with PBS, 5-aminolevulinic acid (ALA), AFeC FANDs upon 635 nm laser at different time intervals. e Tumor volumes of mice with various treatments during 14 days. f Weights of the tumors extracted from mice in varied groups at the end of therapy. g Photographs of A549 tumor-bearing mice in different groups before and after 14 day-treatments. h Body weights of mice in various groups during 14 day-therapy. i Hematoxylin and eosin (H&E), reactive oxygen species (ROS), lipoxygenase enzyme (FACL4), and glutathione peroxidase 4 (GPX4) staining of tumors from mice in different groups. Scale bar: 50 μm. The results in (i) were representative of three independent mice. Data in (d–f, h) were presented as mean ± SD, n = 3 biologically independent mice in (d), n = 6 biologically independent mice in (e, f, h). P values were calculated by two-tailed unpaired t-test. Source data were provided in the Source Data file.CC BY · PubMed Central
Fig. 7 In vivo safety assessments of the AFeC FANDs. a Hematoxylin and eosin (H&E) staining of major organs collected from mice after different treatments. b The blood parameter and c serum biochemistry analysis of mice in various groups. The results in (a) were representative of three independent mice. Data in (b, c) are presented as mean ± SD, n = 4 biologically independent mice. Source data are provided in the Source Data file.
Fig. 7 In vivo safety assessments of the AFeC FANDs. a Hematoxylin and eosin (H&E) staining of major organs collected from mice after different treatments. b The blood parameter and c serum biochemistry analysis of mice in various groups. The results in (a) were representative of three independent mice. Data in (b, c) are presented as mean ± SD, n = 4 biologically independent mice. Source data are provided in the Source Data file.CC BY · PubMed Central

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Metadata

Authors
Fang, F., Wang, S., Song, Y., Sun, M., Chen, W.-C., Zhao, D., & Zhang, J.
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2023-03-25
Volume
14
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-023-37315-0
PMC
PMC10039359
Cited by
112
References
1
Language
en
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