Issue

Vol. 17 (2025)

Multifunctional and Scalable Nanoparticles for Bimodal Image-Guided Phototherapy in Bladder Cancer Treatment

https://doi.org/10.1007/s40820-025-01717-0
Menghuan Tang
Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, CA 95817, USA
Sohaib Mahri
Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, CA 95817, USA
Ya‑Ping Shiau
Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, CA 95817, USA
Tasneem Mukarrama
Department of Biomedical Engineering, University of California Davis, Davis, CA 95616, USA
Rodolfo Villa
Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, CA 95817, USA
Qiufang Zong
Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, CA 95817, USA
Kelsey Jane Racacho
Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, CA 95817, USA
Yangxiong Li
Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, CA 95817, USA
Yunyoung Lee
Department of Biomedical Engineering, University of California Davis, Davis, CA 95616, USA
Yanyu Huang
Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, CA 95817, USA
Zhaoqing Cong
Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, CA 95817, USA
Jinhwan Kim
Department of Biomedical Engineering, University of California Davis, Davis, CA 95616, USA
Yuanpei Li
Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, University of California Davis, Sacramento, CA 95817, USA
Tzu‑Yin Lin
Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis, Sacramento, CA 95817, USA

Corresponding Author: Tzu‑Yin Lin

tylin@ucdavis.edu

Nano-Micro Letters, Vol. 17 (2025), Article Number: 222

Abstract

Rational design of multifunctional nanoplatforms capable of combining therapeutic effects with real-time monitoring of drug distribution and tumor status is emerging as a promising approach in cancer nanomedicine. Here, we introduce pyropheophorbide a–bisaminoquinoline conjugate lipid nanoparticles (PPBC LNPs) as a bimodal system for image-guided phototherapy in bladder cancer treatment. PPBC LNPs not only demonstrate both powerful photodynamic and photothermal effects upon light activation, but also exhibit potent autophagy blockage, effectively inducing bladder cancer cell death. Furthermore, PPBC LNPs possess remarkable photoacoustic (PA) and fluorescence (FL) imaging capabilities, enabling imaging with high-resolution, deep tissue penetration and high sensitivity for tracking drug biodistribution and phototherapy efficacy. Specifically, PA imaging confirms the efficient accumulation of PPBC LNPs within tumor and predicts therapeutic outcomes of photodynamic therapy, while FL imaging confirms their prolonged retention at the tumor site for up to 6 days. PPBC LNPs significantly suppress bladder tumor growth, with several tumors completely ablated following just two doses of the nanoparticles and laser treatment. Additionally, PPBC LNPs were formulated with lipid-based excipients and assembled using microfluidic technology to enhance biocompatibility, stability, and scalability, showing potential for clinical translation. This versatile nanoparticle represents a promising candidate for further development in bladder cancer therapy.


Highlights:
1 Pyropheophorbide a–bisaminoquinoline conjugate lipid nanoparticles (PPBC LNPs), formulated with lipid-based excipients and assembled using microfluidics, exhibit excellent biocompatibility and stability, indicating promise for clinical applications.
2 PPBC LNPs possess remarkable photoacoustic and fluorescence imaging capabilities, enabling high-resolution, deep tissue penetration and high sensitivity imaging for tracking drug biodistribution and phototherapy efficacy.

Keywords

Image-guided phototherapy Photodynamic and photothermal therapy Bladder cancer treatment Photoacoustic imaging Microfluidics-aided production
Tang, Menghuan, Sohaib Mahri, Ya‑Ping Shiau, Tasneem Mukarrama, Rodolfo Villa, Qiufang Zong, Kelsey Jane Racacho, Yangxiong Li, Yunyoung Lee, Yanyu Huang, Zhaoqing Cong, Jinhwan Kim, Yuanpei Li, and Tzu‑Yin Lin. 2025. “Multifunctional and Scalable Nanoparticles for Bimodal Image-Guided Phototherapy in Bladder Cancer Treatment”. Nano-Micro Letters 17 (April):222. https://doi.org/10.1007/s40820-025-01717-0.
Download Citation
Endnote/Zotero/Mendeley (RIS)
BibTeX
References
  1. L. Dong, C. Hu, Z. Ma, Y. Huang, G. Shelley et al., Urinary extracellular vesicle-derived miR-126-3p predicts lymph node invasion in patients with high-risk prostate cancer. Med. Oncol. 41(7), 169 (2024). https://doi.org/10.1007/s12032-024-02400-x
  2. J. Dobruch, M. Oszczudłowski, Bladder cancer: current challenges and future directions. Medicina 57(8), 749 (2021). https://doi.org/10.3390/medicina57080749
  3. Y.-H. Jin, X.-T. Zeng, T.-Z. Liu, Z.-M. Bai, Z.-L. Dou et al., Treatment and surveillance for non-muscle-invasive bladder cancer: a clinical practice guideline (2021 edition). Mil. Med. Res. 9(1), 44 (2022). https://doi.org/10.1186/s40779-022-00406-y
  4. R.C. Md, M. Shelley, S. Selph, M. David, I. Buckley, K.S. Gustafson, J.C. Griffin et al., Treatment of muscle-invasive bladder cancer: a systematic review. Cancer 122(6), 842–851 (2016). https://doi.org/10.1002/cncr.29843
  5. R. Contieri, P.J. Hensley, W.S. Tan, V. Grajales, K. Bree et al., Oncological outcomes for patients with European association of urology very high-risk non-muscle-invasive bladder cancer treated with Bacillus calmette-guérin or early radical cystectomy. Eur. Urol. Oncol. 6(6), 590–596 (2023). https://doi.org/10.1016/j.euo.2023.07.012
  6. T.W. Flaig, P.E. Spiess, N. Agarwal, R. Bangs, S.A. Boorjian et al., Bladder cancer, version 3.2020, NCCN clinical practice guidelines in oncology. J. Natl. Compr. Cancer Netw. 18(3), 329–354 (2020). https://doi.org/10.6004/jnccn.2020.0011
  7. J.Y. Teoh, A.M. Kamat, P.C. Black, P. Grivas, S.F. Shariat et al., Recurrence mechanisms of non-muscle-invasive bladder cancer - a clinical perspective. Nat. Rev. Urol. 19(5), 280–294 (2022). https://doi.org/10.1038/s41585-022-00578-1
  8. H.Y. Yoon, H.M. Yang, C.H. Kim, Y.T. Goo, M.J. Kang et al., Current status of the development of intravesical drug delivery systems for the treatment of bladder cancer. Expert Opin. Drug Deliv. 17(11), 1555–1572 (2020). https://doi.org/10.1080/17425247.2020.1810016
  9. J.-L. Lu, Q.-D. Xia, Y.-H. Lu, Z. Liu, P. Zhou et al., Efficacy of intravesical therapies on the prevention of recurrence and progression of non-muscle-invasive bladder cancer: a systematic review and network meta-analysis. Cancer Med. 9(21), 7800–7809 (2020). https://doi.org/10.1002/cam4.3513
  10. T.Y. Lin, Y. Li, Q. Liu, J.L. Chen, H. Zhang et al., Novel theranostic nanoporphyrins for photodynamic diagnosis and trimodal therapy for bladder cancer. Biomaterials 104, 339–351 (2016). https://doi.org/10.1016/j.biomaterials.2016.07.026
  11. P. Agostinis, K. Berg, K.A. Cengel, T.H. Foster, A.W. Girotti et al., Photodynamic therapy of cancer: an update. CA A Cancer J. Clin. 61(4), 250–281 (2011). https://doi.org/10.3322/caac.20114
  12. D.E.J.G.J. Dolmans, D. Fukumura, R.K. Jain, Photodynamic therapy for cancer. Nat. Rev. Cancer 3(5), 380–387 (2003). https://doi.org/10.1038/nrc1071
  13. K.M.M. Rahman, P. Giram, B.A. Foster, Y. You, Photodynamic therapy for bladder cancers, a focused review. Photochem. Photobiol. 99(2), 420–436 (2023). https://doi.org/10.1111/php.13726
  14. L. Tran, J.-F. Xiao, N. Agarwal, J.E. Duex, D. Theodorescu, Advances in bladder cancer biology and therapy. Nat. Rev. Cancer 21(2), 104–121 (2021). https://doi.org/10.1038/s41568-020-00313-1
  15. D. van Straten, V. Mashayekhi, H.S. de Bruijn, S. Oliveira, D.J. Robinson, Oncologic photodynamic therapy: basic principles, current clinical status and future directions. Cancers 9(2), 19 (2017). https://doi.org/10.3390/cancers9020019
  16. J. Nam, S. Son, L.J. Ochyl, R. Kuai, A. Schwendeman et al., Chemo-photothermal therapy combination elicits anti-tumor immunity against advanced metastatic cancer. Nat. Commun. 9(1), 1074 (2018). https://doi.org/10.1038/s41467-018-03473-9
  17. H.S. Han, K.Y. Choi, Advances in nanomaterial-mediated photothermal cancer therapies: toward clinical applications. Biomedicines 9(3), 305 (2021). https://doi.org/10.3390/biomedicines9030305
  18. M. Overchuk, R.A. Weersink, B.C. Wilson, G. Zheng, Photodynamic and photothermal therapies: synergy opportunities for nanomedicine. ACS Nano 17(9), 7979–8003 (2023). https://doi.org/10.1021/acsnano.3c00891
  19. P.A. Sutton, M.A. van Dam, R.A. Cahill, S. Mieog, K. Polom et al., Fluorescence-guided surgery: comprehensive review. BJS Open (2023). https://doi.org/10.1093/bjsopen/zrad049
  20. M.T. Olson, Q.P. Ly, A.M. Mohs, Fluorescence guidance in surgical oncology: challenges, opportunities, and translation. Mol. Imag. Biol. 21(2), 200–218 (2019). https://doi.org/10.1007/s11307-018-1239-2
  21. X. Zhang, Y. Wu, L. Chen, J. Song, H. Yang, Optical and photoacoustic imaging in vivo: opportunities and challenges. Chem. Biomed. Imag. 1(2), 99–109 (2023). https://doi.org/10.1021/cbmi.3c00009
  22. M. Kim, K.P. Kubelick, D. Vanderlaan, D. Qin, J. Lee et al., Coupling gold nanospheres into nanochain constructs for high-contrast, longitudinal photoacoustic imaging. Nano Lett. 24(24), 7202–7210 (2024). https://doi.org/10.1021/acs.nanolett.4c00992
  23. P. Beard, Biomedical photoacoustic imaging. Interface Focus. 1(4), 602–631 (2011). https://doi.org/10.1098/rsfs.2011.0028
  24. M. Mehrmohammadi, S. Joon Yoon, D. Yeager, S.Y. Emelianov, Photoacoustic imaging for cancer detection and staging. Curr. Mol. Imag. 2(1), 89–105 (2013). https://doi.org/10.2174/2211555211302010010
  25. M. Li, Y. Tang, J. Yao, Photoacoustic tomography of blood oxygenation: a mini review. Photoacoustics 10, 65–73 (2018). https://doi.org/10.1016/j.pacs.2018.05.001
  26. S. Jung, J. Lee, J. Lim, J. Suh, T. Kim et al., Polymeric nanops controlled by on-chip self-assembly enhance cancer treatment effectiveness. Adv. Healthc. Mater. 9(22), e2001633 (2020). https://doi.org/10.1002/adhm.202001633
  27. S.J. Shepherd, D. Issadore, M.J. Mitchell, Microfluidic formulation of nanops for biomedical applications. Biomaterials 274, 120826 (2021). https://doi.org/10.1016/j.biomaterials.2021.120826
  28. S. Gimondi, H. Ferreira, R.L. Reis, N.M. Neves, Microfluidic devices: a tool for nanop synthesis and performance evaluation. ACS Nano 17(15), 14205–14228 (2023). https://doi.org/10.1021/acsnano.3c01117
  29. Y. Liu, G. Yang, Y. Hui, S. Ranaweera, C.X. Zhao, Microfluidic nanops for drug delivery. Small 18(36), 2106580 (2022). https://doi.org/10.1002/smll.202106580
  30. Z. Ma, K. Lin, M. Tang, M. Ramachandran, R. Qiu et al., A pH-driven small-molecule nanotransformer hijacks lysosomes and overcomes autophagy-induced resistance in cancer. Angew. Chem. Int. Ed. 61(35), e202204567 (2022). https://doi.org/10.1002/anie.202204567
  31. H. Liao, Y. Chu, S. Liao, Y. He, Y. Ma et al., Double safety guarantees: Food-grade photothermal complex with a pH-triggered NIR absorption from zero to one. Fundam. Res. 4(5), 1157–1166 (2022). https://doi.org/10.1016/j.fmre.2022.06.004
  32. D. Xi, M. Xiao, J. Cao, L. Zhao, N. Xu et al., NIR light-driving barrier-free group rotation in nanops with an 88.3% photothermal conversion efficiency for photothermal therapy. Adv. Mater. 32(11), e1907855 (2020). https://doi.org/10.1002/adma.201907855
  33. W.-C. Luo, A.O. Beringhs, R. Kim, W. Zhang, S.M. Patel et al., Impact of formulation on the quality and stability of freeze-dried nanops. Eur. J. Pharm. Biopharm. 169, 256–267 (2021). https://doi.org/10.1016/j.ejpb.2021.10.014
  34. E. Trenkenschuh, W. Friess, Freeze-drying of nanops: how to overcome colloidal instability by formulation and process optimization. Eur. J. Pharm. Biopharm. 165, 345–360 (2021). https://doi.org/10.1016/j.ejpb.2021.05.024
  35. N. Beniwal, A. Verma, C.L. Putta, A.K. Rengan, Recent trends in bio-nanomaterials and non-invasive combinatorial approaches of photothermal therapy against cancer. Nanotheranostics 8(2), 219–238 (2024). https://doi.org/10.7150/ntno.91356
  36. V. Raja Solomon, H. Lee, Chloroquine and its analogs: a new promise of an old drug for effective and safe cancer therapies. Eur. J. Pharmacol. 625(1–3), 220–233 (2009). https://doi.org/10.1016/j.ejphar.2009.06.063
  37. Z. Ma, J. Li, K. Lin, M. Ramachandran, D. Zhang et al., Pharmacophore hybridisation and nanoscale assembly to discover self-delivering lysosomotropic new-chemical entities for cancer therapy. Nat. Commun. 11(1), 4615 (2020). https://doi.org/10.1038/s41467-020-18399-4
  38. S. Sukseree, L. László, F. Gruber, S. Bergmann, M.S. Narzt et al., Filamentous aggregation of sequestosome-1/p62 in brain neurons and neuroepithelial cells upon Tyr-cre-mediated deletion of the autophagy gene Atg7. Mol. Neurobiol. 55(11), 8425–8437 (2018). https://doi.org/10.1007/s12035-018-0996-x
  39. T. Aki, K. Unuma, K. Noritake, N. Hirayama, T. Funakoshi et al., Formation of high molecular weight p62 by CORM-3. PLoS ONE 14(1), e0210474 (2019). https://doi.org/10.1371/journal.pone.0210474
  40. D.R. Mokoena, B.P. George, H. Abrahamse, Photodynamic therapy induced cell death mechanisms in breast cancer. Int. J. Mol. Sci. 22(19), 10506 (2021). https://doi.org/10.3390/ijms221910506
  41. K. Lin, Z. Ma, J. Li, M. Tang, A. Lindstrom et al., Single small molecule-assembled mitochondria targeting nanofibers for enhanced photodynamic cancer therapy in vivo. Adv. Funct. Mater. 31(10), 2008460 (2021). https://doi.org/10.1002/adfm.202008460
  42. H. Kurokawa, H. Ito, M. Terasaki, H. Matsui, Hyperthermia enhances photodynamic therapy by regulation of HCP1 and ABCG2 expressions via high level ROS generation. Sci. Rep. 9(1), 1638 (2019). https://doi.org/10.1038/s41598-018-38460-z
  43. M. Tang, K. Lin, M. Ramachandran, L. Li, H. Zou et al., A mitochondria-targeting lipid–small molecule hybrid nanop for imaging and therapy in an orthotopic glioma model. Acta Pharm. Sin. B 12(6), 2672–2682 (2022). https://doi.org/10.1016/j.apsb.2022.04.005
  44. M.-S. Hwang, C.T. Schwall, E. Pazarentzos, C. Datler, N.N. Alder et al., Mitochondrial Ca2+ influx targets cardiolipin to disintegrate respiratory chain complex II for cell death induction. Cell Death Differ. 21(11), 1733–1745 (2014). https://doi.org/10.1038/cdd.2014.84
  45. S. Romero-Garcia, H. Prado-Garcia, Mitochondrial calcium: Transport and modulation of cellular processes in homeostasis and cancer (Review). Int. J. Oncol. 54(4), 1155–1167 (2019). https://doi.org/10.3892/ijo.2019.4696
  46. T. Rodrigues, S. Piccirillo, S. Magi, A. Preziuso, V. Dos Santos Ramos et al., Control of Ca2+ and metabolic homeostasis by the Na+/Ca2+ exchangers (NCXs) in health and disease. Biochem. Pharmacol. 203, 115163 (2022). https://doi.org/10.1016/j.bcp.2022.115163
  47. K. Siwawannapong, R. Zhang, H. Lei, Q. Jin, W. Tang et al., Ultra-small pyropheophorbide-a nanodots for near-infrared fluorescence/photoacoustic imaging-guided photodynamic therapy. Theranostics 10(1), 62–73 (2020). https://doi.org/10.7150/thno.35735
  48. D. Baimanov, Z. Song, Z. Zhang, L. Sun, Q. Yuan et al., Preferred lung accumulation of polystyrene nanoplastics with negative charges. Nano Lett. 24(41), 12857–12865 (2024). https://doi.org/10.1021/acs.nanolett.4c03245
  49. H. Huang, R. Hernandez, J. Geng, H. Sun, W. Song et al., A porphyrin-PEG polymer with rapid renal clearance. Biomaterials 76, 25–32 (2016). https://doi.org/10.1016/j.biomaterials.2015.10.049
  50. V. Agrahari, V. Agrahari, Facilitating the translation of nanomedicines to a clinical product: challenges and opportunities. Drug Discov. Today 23(5), 974–991 (2018). https://doi.org/10.1016/j.drudis.2018.01.047
  51. C.L. Saw, P.W. Heng, M. Olivo, Potentiation of the photodynamic action of hypericin. J. Environ. Pathol. Toxicol. Oncol. 27(1), 23–33 (2008). https://doi.org/10.1615/jenvironpatholtoxicoloncol.v27.i1.30
  52. B.W. Henderson, T.M. Busch, L.A. Vaughan, N.P. Frawley, D. Babich et al., Photofrin photodynamic therapy can significantly deplete or preserve oxygenation in human basal cell carcinomas during treatment, depending on fluence rate. Cancer Res. 60(3), 525–529 (2000) PMID: 10676629
  53. M.F. Wei, M.W. Chen, K.C. Chen, P.J. Lou, S.Y. Lin et al., Autophagy promotes resistance to photodynamic therapy-induced apoptosis selectively in colorectal cancer stem-like cells. Autophagy 10(7), 1179–1192 (2014). https://doi.org/10.4161/auto.28679
  54. B.Q. Spring, I. Rizvi, N. Xu, T. Hasan, The role of photodynamic therapy in overcoming cancer drug resistance. Photochem. Photobiol. Sci. 14(8), 1476–1491 (2015). https://doi.org/10.1039/c4pp00495g
  55. S. Shrivastava, J.J. Mansure, W. Almajed, F. Cury, G. Ferbeyre et al., The role of HMGB1 in radioresistance of bladder cancer. Mol. Cancer Ther. 15(3), 471–479 (2016). https://doi.org/10.1158/1535-7163.MCT-15-0581
  56. E. Konac, Y. Kurman, S. Baltaci, Contrast effects of autophagy in the treatment of bladder cancer. Exp. Biol. Med. 246(3), 354–367 (2021). https://doi.org/10.1177/1535370220959336
  57. P. Tan, H. Cai, Q. Wei, X. Tang, Q. Zhang et al., Enhanced chemo-photodynamic therapy of an enzyme-responsive prodrug in bladder cancer patient-derived xenograft models. Biomaterials 277, 121061 (2021). https://doi.org/10.1016/j.biomaterials.2021.121061
  58. G. Li, S. Yuan, D. Deng, T. Ou, Y. Li et al., Fluorinated polyethylenimine to enable transmucosal delivery of photosensitizer-conjugated catalase for photodynamic therapy of orthotopic bladder tumors postintravesical instillation. Adv. Funct. Mater. 29(40), 1901932 (2019). https://doi.org/10.1002/adfm.201901932
  59. A. Winnicka, J. Brzeszczyńska, J. Saluk, P. Wigner-Jeziorska, Nanomedicine in bladder cancer therapy. Int. J. Mol. Sci. 25(19), 10388 (2024). https://doi.org/10.3390/ijms251910388
  60. J. Zhou, J.V. Jokerst, Photoacoustic imaging with fiber optic technology: a review. Photoacoustics 20, 100211 (2020). https://doi.org/10.1016/j.pacs.2020.100211
  61. K. Kim, J.Y. Youm, E.H. Lee, O. Gulenko, M. Kim et al., Tapered catheter-based transurethral photoacoustic and ultrasonic endoscopy of the urinary system. Opt. Express 30(15), 26169–26181 (2022). https://doi.org/10.1364/OE.461855
  62. J. Park, S. Choi, F. Knieling, B. Clingman, S. Bohndiek et al., Clinical translation of photoacoustic imaging. Nat. Rev. Bioeng. (2024). https://doi.org/10.1038/s44222-024-00240-y
  63. J. Kim, D. Heo, S. Cho, M. Ha, J. Park et al., Enhanced dual-mode imaging: superior photoacoustic and ultrasound endoscopy in live pigs using a transparent ultrasound transducer. Sci. Adv. 10(47), eadq9960 (2024). https://doi.org/10.1126/sciadv.adq9960
  64. H. Nie, H. Luo, L. Chen, Q. Zhu, A coregistered ultrasound and photoacoustic imaging protocol for the transvaginal imaging of ovarian lesions. J. Vis. Exp. 193, e64864 (2023). https://doi.org/10.3791/64864
  65. D. Oh, H. Kim, M. Sung, C. Kim, Video-rate endocavity photoacoustic/harmonic ultrasound imaging with miniaturized light delivery. J. Biomed. Opt. 29(Suppl 1), S11528 (2024). https://doi.org/10.1117/1.JBO.29.S1.S11528
  66. G. Yang, E. Amidi, W. Chapman, S. Nandy, A. Mostafa et al., Co-registered photoacoustic and ultrasound imaging of human colorectal cancer. J. Biomed. Opt. 24(12), 1–13 (2019). https://doi.org/10.1117/1.JBO.24.12.121913
  67. S.R. Kothapalli, G.A. Sonn, J.W. Choe, A. Nikoozadeh, A. Bhuyan et al., Simultaneous transrectal ultrasound and photoacoustic human prostate imaging. Sci. Transl. Med. 11(507), eaav2169 (2019). https://doi.org/10.1126/scitranslmed.aav2169
  68. Y. Liang, W. Fu, Q. Li, X. Chen, H. Sun et al., Optical-resolution functional gastrointestinal photoacoustic endoscopy based on optical heterodyne detection of ultrasound. Nat. Commun. 13(1), 7604 (2022). https://doi.org/10.1038/s41467-022-35259-5
Read More
Author biographies are not available.
Download this PDF file
PDF SUPPLEMENTARY FILE
Statistic
Read Counter : 390 Download : 295