Key Takeaways & Executive Findings
- •• PPBC LNPs integrate photodynamic and photothermal therapy with autophagy blockage, effectively inducing bladder cancer cell death. • The nanoparticles enable bimodal photoacoustic and fluorescence imaging, allowing high-resolution, deep-tissue tracking of drug biodistribution and therapeutic response. • Two doses of PPBC LNPs combined with laser treatment led to complete ablation of several bladder tumors, demonstrating potent antitumor efficacy. • Formulated with lipid excipients via microfluidics, PPBC LNPs exhibit excellent biocompatibility, stability, and scalability, supporting clinical translation.
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.
1. Introduction
Bladder cancer is a prevalent urological malignancy, with 614,298 new cases and 220,596 deaths reported globally in 2022 [1, 2]. Standard treatments include transurethral resection of bladder tumor (TURBT), intravesical chemotherapy, and immunotherapy for non-muscle invasive bladder cancer (NMIBC), as well as radical cystectomy with chemotherapy for muscle invasive bladder cancer [3, 4]. Despite these interventions, up to 30%–80% of patients experience tumor recurrence within 5 years [5, 6]. Current therapies face several challenges: TURBT or cystectomy alone is usually insufficient to prevent recurrence, while intravesical treatments suffer from poor drug retention, systemic toxicity, and limited penetration into bladder tissue [7, 8]. Chemotherapeutic agents like mitomycin C and Bacillus Calmette–Guérin immunotherapy, although effective, can cause significant side effects and may lead to drug resistance [9].
Photodynamic therapy (PDT) offers a minimally invasive option for bladder cancer treatment [10, 11]. The bladder’s accessibility and the feasibility of delivering light through optical fibers make it suitable for PDT. PDT was clinically approved for bladder cancer treatment in 1993 with the photosensitizer Photofrin® [12]. More recently, TLD-1433, a polypyridyl Ru (II) complex, has entered clinical trials for NMIBC treatment [13, 14]. However, PDT suffers from intrinsic limitations, including oxygen dependence, poor selectivity, limited bioavailability, and poor pharmacokinetic properties, all of which constrain its clinical efficacy [10, 15]. Photothermal therapy (PTT) has emerged as an alternative for treating advanced tumors [16, 17]. PTT employs photosensitizers (PSs) to convert laser energy into heat, inducing hyperthermia-mediated cell death. This oxygen-independent mechanism may overcome the hypoxia-related limitations of PDT. Therefore, there is growing interest in developing dual-modal PSs that can elicit both PDT and PTT effects for bladder cancer treatment [18].
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Menghuan Tang, 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, Tzu-Yin Lin (2025). Multifunctional and Scalable Nanoparticles for Bimodal Image-Guided Phototherapy in Bladder Cancer Treatment. Nano-Micro Letters. https://doi.org/10.1007/s40820-025-01717-0
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Frequently Asked Questions
What are PPBC LNPs and how are they used in bladder cancer treatment?
PPBC LNPs are pyropheophorbide a–bisaminoquinoline conjugate lipid nanoparticles that combine photodynamic and photothermal therapy with autophagy blockage. They are designed for image-guided phototherapy, enabling bimodal photoacoustic and fluorescence imaging to track drug distribution and therapeutic efficacy in bladder cancer.
How do PPBC LNPs enhance imaging and therapy?
PPBC LNPs exhibit strong photoacoustic and fluorescence signals, allowing high-resolution, deep-tissue imaging. They also generate both reactive oxygen species (PDT) and heat (PTT) upon light activation, leading to effective cancer cell death. Their autophagy-blocking property further enhances their antitumor activity.
What is the significance of using microfluidics for PPBC LNP production?
Microfluidics enables scalable and reproducible assembly of PPBC LNPs with lipid-based excipients, ensuring excellent biocompatibility, stability, and uniformity. This manufacturing approach supports clinical translation by facilitating large-scale production.
What were the key results of the study?
The study demonstrated that PPBC LNPs significantly suppressed bladder tumor growth in vivo, with several tumors completely ablated after just two doses combined with laser treatment. The nanoparticles also showed prolonged retention at the tumor site for up to 6 days, as confirmed by fluorescence imaging.
What are the potential clinical applications of PPBC LNPs?
PPBC LNPs hold promise for clinical translation in bladder cancer therapy, offering a multifunctional platform for image-guided phototherapy. Their ability to combine therapeutic and imaging functions could improve treatment precision and monitoring, potentially reducing recurrence rates.
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