Hafnium oxide nanoparticles

RT-NBTXR3 followed by anti-PD-1 demonstrated favorable safety profile, disease control and tumor response in patients both naïve and resistant to anti-PD-1, suggesting that NBTXR3 may prime the immune system before checkpoint therapySeveral clinical milestones expected over the next 12-18 months including updated data in pancreatic, and head and neck cancer, and initial data in esophageal and lung cancer€66.3 million in cash and cash equivalents as of June 30, 2024, with a cash runway extended into Q4 2025 PARIS and CAMBRIDGE, Mass., Sept. 18, 2024 (GLOBE NEWSWIRE) -- NANOBIOTIX (Euronext: NANO - NASDAQ: NBTX - the “Company”), a late-clinical stage biotechnology company pioneering nanoparticle-based approaches to expand treatment possibilities for patients with cancer and other major diseases, provided an update on operational progress and announced its half year financial results for the six-month period ended June 30, 2024. “We continue to make strong progress advancing our nanoparticle-based therapeutic approach with lead candidate NBTXR3, which is part of our global licensing agreement with Janssen Pharmaceutica NV, a Johnson & Johnson company. The agreement is designed to realize significant therapeutic and market opportunities in solid tumor cancers worldwide, starting with lung and head and neck. We also continue to establish additional expansion opportunities across multiple cancer settings as part of our ongoing collaboration with MD Anderson,” said Laurent Levy, co-founder of Nanobiotix and chairman of the executive board. “The potential of NBTXR3 to prime immune activity before an anti-PD-1 inhibitor was further reinforced with new data from Study 1100 announced at the Annual Meeting of American Society for Clinical Oncology (ASCO) showing disease control and tumor response in patients with head and neck cancer that are naïve or resistant to prior anti-PD-1 therapy. We expect several clinical milestones over the next 12-18 months that, would further advance and broaden the potential patient population for NBTXR3 including updated data in pancreatic and head and neck cancer, and initial data in esophageal and lung cancer.” First Half 2024 Operational Highlights, Pipeline Status and Expected Milestones Strengthened Supervisory Board with the nominations of Dr. Margaret A. Liu and Ms. Anat Naschitz as board observers, two key additions intended to further equip the Company for sustainable long-term growth. Dr. Liu brings a wealth of experience in US and international academia, pharmaceuticals, biotechnology and public policy, and Ms. Naschitz brings world-class expertise in raising and deploying capital to support disruptive innovation for the benefit of patients, healthcare professionals and investors. Achieved a NANORAY-312 operational milestone as part of global exclusive licensing, co-development, and commercialization agreement with Janssen Pharmaceutica NV, a Johnson & Johnson company, for the investigational, potential first-in-class radioenhancer NBTXR3 and subsequently received the $20 million payment. Locally Advanced Head and Neck Squamous Cell Carcinoma (LA-HNSCC): Local Control as Single Agent Activated by Radiotherapy (RT) NANORAY-312, a pivotal, global, randomized Phase 3 trial evaluating RT-activated NBTXR3 ± cetuximab vs RT ± cetuximab in elderly patients ineligible for cisplatin chemotherapy Interim analysis to be reported after both the requisite number of events has occurred and the last patient is recruited, expected by 1H2026Ongoing transfer of the sponsorship to Janssen to facilitate preparations for potentially positive trial results and subsequent steps Study 102, a successfully completed Phase 1 dose escalation and expansion trial evaluating RT-activated NBTXR3 in patients ineligible for cisplatin chemotherapy or intolerant to cetuximab. Final results showed topline safety and efficacy data supporting robust anti-tumor activity and a well-tolerated profile in elderly patients with a high burden of comorbidity (n=56) Non-Small Cell Lung Cancer (NSCLC) Janssen-led randomized Phase 2 study evaluating NBTXR3 + chemoradiation followed by anti-PD-L1 for patients with inoperable, stage 3 NSCLC Study may proceed letter received from the Food and Drug Administration (FDA)First patient randomized is the next expected milestone Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma (R/M HNSCC): Priming Immune Response Followed by an Anti-PD-1 Treatment: Study 1100, a Phase 1 dose escalation and expansion trial evaluating RT-activated NBTXR3 followed by an anti-PD-1 as a second-or-later line treatment in patients with advanced cancers Completed dose escalation part – ongoing dose expansion part. New data in R/M HNSCC Naïve or Resistant to Anti-PD-1 presented at ASCO: Favorable safety and feasibility in 68 heavily pre-treated patients with R/M-HNSCC (Intention-to-Treat population; “ITT”)48% overall response rate (ORR) in evaluable anti-PD-1 naïve patients (n=25); 28% ORR in evaluable anti-PD-1 resistant patients (n=25) as per RECIST 1.176% disease control rate (DCR) in evaluable naïve patients; 68% DCR in evaluable resistant patients as per RECIST 1.1Preliminary review of survival data in ITT anti-PD-1 naïve patients (n=33) showed mPFS of 7.3 months and mOS of 26.2 monthsITT anti-PD-1 resistant patients (n=35) showed mPFS of 4.2 months and mOS of 7.8 months Initial data from immunotherapy resistant patients with multiple primary tumors expected in 2025Data supports further evaluation in randomized clinical trials which may include a potential registrational pathway for NBTXR3 in combination with an immunotherapy. Pancreatic, Lung and Others: Expanding NBTXR3 Opportunity Through a Strategic Collaboration with The University of Texas MD Anderson Cancer Center to Validate Tumor-Agnostic, Combination-Agnostic Therapeutic Profiles Five ongoing clinical trials in advanced solid tumors: Advanced Solid Tumors with Lung or Liver Metastases: Phase 1/2 study (NCT05039632) of RT-activated NBTXR3 plus an anti-PD-1/L-1 immune checkpoint inhibitorRecurrent or Metastatic Head and Neck Cancer: Phase 2 study (NCT04862455) of RT-activated NBTXR3 in combination with anti-PD-1Inoperable Non-Small Cell Lung Cancer (NSCLC): Phase 1 study (NCT04505267) of single agent RT-activated NBTXR3 Dose escalation completed and dose expansion ongoing. Established RP2D after determination of injection feasibility and observation of a favorable safety profile. Esophageal Cancer: Phase 1 study (NCT04615013) of RT-activated NBTXR3 in combination with chemotherapy Pancreatic Cancer: Phase 1b study (NCT04484909) of RT-activated NBTXR3 after cytotoxic chemotherapy for patients with locally advanced pancreatic cancer (LAPC) Multiple expected clinical milestones: Updated Phase 1b dose escalation data in pancreatic cancer expected 2H2024Initial Phase 1 dose escalation data in inoperable, recurrent NSCLC amenable to re-irradiation expected 1H2025Completion of dose escalation in Phase 1b/2 trial in esophageal cancer expected in 2024, initiation of dose expansion part, and presentation of first data in 2025 Half Year 2024 Financial Results Revenue and Other Income: Revenue and other income has increased for the six months ended June 30, 2024, to €9.3 million, compared to €3.3 million for the six months ended June 30, 2023, primarily resulting from services and product supply revenue linked to the exclusive licensing, co-development, and commercialization agreement with Janssen Pharmaceutica NV executed on July 7, 2023. Research and Development (“R&D”) Expenses: R&D expenses consist primarily of preclinical, clinical and manufacturing expenses related to the development of NBTXR3. These expenses for the six months ended June 30, 2024, were €22.0 million, primarily driven by an increase of the clinical development activities in NANORAY-312, compared to €17.8 million for the six months ended June 30, 2023. Selling, General and Administrative (“SG&A”) Expenses: SG&A expenses consist primarily of administrative employee-related expenses, legal and other professional fees, patent filing and maintenance fees, and insurance. Total SG&A expenses for the six months ended June 30, 2024, were €10.8 million, compared to €10.9 million for the prior-year six-month period. Net loss: Net loss attributable to common shareholders for the six months ended June 30, 2024, was €21.9 million, or a €0.46 basic loss per share. This compares to a net loss attributable to common shareholders of €28.1 million, or €0.80 basic loss per share, for the same period in 2023. Cash and Cash Equivalents: Cash and cash equivalents as of June 30, 2024, were €66.3 million, compared to €75.3 million as of December 31, 2023. Based on the current operating plan and financial projections, we anticipate that the cash and cash equivalents of €66.3 million as of June 30, 2024, will now fund our operations into Q4 2025, compared to Q3 2025 in prior guidance. Availability of the Half Year 2024 Financial Reports The 2024 half-year financial report has been filed with the French financial market authority (Autorité des marchés financiers). It is available to the public on the Company’s website, www.nanobiotix.com. About NBTXR3 NBTXR3 is a novel, potentially first-in-class oncology product composed of functionalized hafnium oxide nanoparticles that is administered via one-time intratumoral injection and activated by radiotherapy. Its proof-of-concept was achieved in soft tissue sarcomas for which the product received a European CE mark in 2019. The product candidate’s physical mechanism of action (MoA) is designed to induce significant tumor cell death in the injected tumor when activated by radiotherapy, subsequently triggering adaptive immune response and long-term anti-cancer memory. Given the physical MoA, Nanobiotix believes that NBTXR3 could be scalable across any solid tumor that can be treated with radiotherapy and across any therapeutic combination, particularly immune checkpoint inhibitors. Radiotherapy-activated NBTXR3 is being evaluated across multiple solid tumor indications as a single agent or in combination with anti-PD-1 immune checkpoint inhibitors, including in NANORAY-312—a global, randomized Phase 3 study in locally advanced head and neck squamous cell cancers. In February 2020, the United States Food and Drug Administration granted regulatory Fast Track designation for the investigation of NBTXR3 activated by radiation therapy, with or without cetuximab, for the treatment of patients with locally advanced HNSCC who are not eligible for platinum-based chemotherapy—the same population being evaluated in the Phase 3 study. Given the Company’s focus areas, and balanced against the scalable potential of NBTXR3, Nanobiotix has engaged in a collaboration strategy to expand development of the product candidate in parallel with its priority development pathways. Pursuant to this strategy, in 2019 Nanobiotix entered into a broad, comprehensive clinical research collaboration with The University of Texas MD Anderson Cancer Center to sponsor several Phase 1 and Phase 2 studies evaluating NBTXR3 across tumor types and therapeutic combinations. In 2023, Nanobiotix announced a license agreement for the global co-development and commercialization of NBTXR3 with Janssen Pharmaceutica NV. About NANOBIOTIX Nanobiotix is a late-stage clinical biotechnology company pioneering disruptive, physics-based therapeutic approaches to revolutionize treatment outcomes for millions of patients; supported by people committed to making a difference for humanity. The Company’s philosophy is rooted in the concept of pushing past the boundaries of what is known to expand possibilities for human life. Incorporated in 2003, Nanobiotix is headquartered in Paris, France and is listed on Euronext Paris since 2012 and on the Nasdaq Global Select Market in New York City since December 2020. The Company has subsidiaries in Cambridge, Massachusetts (United States) amongst other locations. Nanobiotix is the owner of more than 25 patent families associated with three (3) nanotechnology platforms with applications in 1) oncology; 2) bioavailability and biodistribution; and 3) disorders of the central nervous system. For more information about Nanobiotix, visit us at www.nanobiotix.com or follow us on LinkedIn and Twitter DisclaimerThis press release contains “forward-looking” statements within the meaning of the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to, statements regarding the use of proceed therefrom, and the period of time through which the Company’s anticipates its financial resources will be adequate to support operations. Words such as “expects”, “intends”, “can”, “could”, “may”, “might”, “plan”, “potential”, “should” and “will” or the negative of these and similar expressions are intended to identify forward-looking statements. These forward-looking statements, which are based on our management’s current expectations and assumptions and on information currently available to management. These forward-looking statements involve known and unknown risks, uncertainties and other factors that could cause actual results to differ materially from those implied by the forward-looking statements, including risks related to Nanobiotix’s business and financial performance, which include the risk that assumptions underlying the Company’s cash runway projections are not realized. Further information on the risk factors that may affect company business and financial performance is included in Nanobiotix’s Annual Report on Form 20-F filed with the SEC on April 24, 2024 under “Item 3.D. Risk Factors”, in Nanobiotix’s 2023 universal registration document filed with the AMF on April 24, 2024, in Nanobiotix’ 2024 semi-annual report under the caption “Supplemental Risk Factor” filed with the SEC on Form 6-K and with AMF on September 18 2024, and subsequent filings Nanobiotix makes with the SEC from time to time which are available on the SEC’s website at www.sec.gov. The forward-looking statements included in this press release speak only as of the date of this press release, and except as required by law, Nanobiotix assumes no obligation to update these forward-looking statements publicly. Contacts NanobiotixCommunications DepartmentBrandon OwensVP, Communications+1 (617) 852-4835contact@nanobiotix.comInvestor Relations DepartmentCraig WestSVP, Investor Relations+1 (617) 583-0211investors@nanobiotix.comMedia RelationsFR – Ulysse CommunicationLaurent Wormser+ 33 (0)6 13 12 04 04lwormser@ulysse-communication.comGlobal – LifeSci AdvisorsKevin Gardner+1 (617) 283-2856kgardner@lifesciadvisors.com Attachment 2024-09-18 -- NBTX -- 1H24 Financial Results -- FINAL

▲8月15-16日 苏州2024生物医药创新者峰会 扫码报名  注：本文不构成任何投资意见和建议，以官方/公司公告为准；本文仅作医疗健康相关药物介绍，非治疗方案推荐（若涉及），不代表平台立场。任何文章转载需得到授权。 摘要：近几十年来，纳米医学的概念有了显著的发展，利用了被称为增强渗透性和滞留（EPR）效应的独特现象。通过将纳米技术原理整合到医学中，这促进了靶向药物递送、成像和个体化治疗的重大进步。许多纳米药物已经被开发并应用于疾病治疗，特别是癌症治疗。最近，纳米医学已经应用于各种先进领域，包括诊断、疫苗、免疫治疗、基因递送和组织工程。多功能纳米药物促进同时给药、治疗监测和成像，允许即时反应和个性化治疗计划。本文综述了纳米材料的主要进展及其在生物和医学领域的潜在应用。与此同时，我们还提到了纳米医学的各种临床转化，以及纳米医学目前在克服临床转化障碍方面所面临的主要挑战。 关键词：纳米医学应用；免疫疗法；治疗的；疫苗开发；基因治疗；组织工程 1. 介绍 1959年，物理学家理查德·费曼在一次关于在原子和分子水平上创造物体的演讲中首次提出了纳米技术的概念。如今，科学家们相信纳米技术是21世纪最有前途的技术进步。他们将其作为一种潜在的研究医疗条件的新方法进行研究。在过去十年中，用于纳米技术研究和开发的公共资金有所增加，这表明纳米技术将迎来一个生产力和繁荣的新时代[1]。此外，纳米医学的应用开辟了以前未开发的潜力，特别是在癌症治疗方面。它提供了精确的靶向，提高了疗效，减少了不良反应。 许多纳米颗粒（NPs），包括脂质体、聚合物NPs和无机NPs，现在在治疗领域提供了益处，包括改善的体外和体内药物稳定性、治疗效果和表面修饰的简易性[2]。最近，生物特异性分子现在可以通过化学或物理技术与NP结合，并且NP可以用于某些生物事件的利用，例如抗体-抗原相互作用、受体-配体相互作用和DNA-DNA杂交[3]。为了将药物输送集中在目标区域并防止酶降解，可以制造工程纳米颗粒（NPs）来控制药物释放并靶向或避免与不同细胞的特定相互作用[2]。尽管纳米颗粒介导的递送方法解决了上述许多问题，但在使用它们时，特别是在纳米颗粒设计方面，有几件事要记住。粒子尺寸、形状、疏水性和表面电荷都对纳米颗粒如何到达目标有敏感的影响。大的纳米颗粒（>100nm）可滞留在细胞外基质（ECM）中，而小的纳米颗粒（<5nm）可在循环过程中从血管中漏出。另一方面，从大约5到100nm的中等大小的纳米颗粒滞留在血流中，并被有效地运输到靶位点。颗粒形状（以及大小）是影响纳米颗粒从淋巴结排出的重要因素。以前的大多数纳米颗粒配方都是球形的，但由于纳米颗粒工程的进步，最近已经生产出了各种不同的形式，包括棒状、棱柱状、立方体、星形和圆盘状。除了颗粒大小和形状，载体的表面电荷对于细胞内化和免疫反应激活也很重要。表面电荷可能对细胞吸收纳米颗粒的能力产生影响。与中性或带负电的纳米颗粒相比，带正电的纳米颗粒通常会引发更强的免疫反应。然而，因为它们经常被捕获在带负电荷的ECM中，所以带正电荷的纳米颗粒显示出降低的组织渗透性[4]。因此，与常规疗法相比，特定工程纳米颗粒可以提供各种益处，包括保护治疗有效载荷免于生物降解，通过主动靶向来靶向肿瘤细胞，这将使脱靶正常细胞毒性最小化，并增强体内稳定性和生物利用度，并且这种纳米颗粒已经被巧妙地编程以在感兴趣的位点释放其有效载荷[5]。此外，纳米材料的具体应用取决于其表面化学（组成）、表面物理（形貌和粗糙度）、表面热力学（润湿性和自由能）和毒理学效应[3]。 在纳米医学应用领域，主要焦点是癌症治疗，利用增强的渗透性和滞留效应（EPR）[6]。EPR效应的历史、机制和未来影响在各种文章和书籍章节中都有详尽的记载[6-12]。这种效应在纳米药物在肿瘤组织内的选择性积聚中起着至关重要的作用，增强了其有效性，同时最大限度地减少了全身暴露和副作用。从本质上讲，EPR效应是指在肿瘤血管独特的解剖和病理生理特征的促进下，大分子药物在肿瘤组织中选择性积聚的现象。这允许大分子药物在全身给药后优先渗透和滞留在实体瘤内。EPR效应的有效性不仅在实验动物模型中得到了证实，而且在人类中也得到了证实，包括肝癌、肾癌和转移性乳腺癌[13-15]。最近对人类肾肿瘤和转移性乳腺癌的研究表明，在超过87%的样本中存在显著的EPR效应，突出了这种效应在抗癌纳米药物进展中的关键作用[13,14]。基于EPR效应，纳米药物表现出许多对靶向癌症治疗有益的特性，而常规小分子抗癌药物则倾向于在正常组织和器官中不加选择地扩散，从而导致全身性不良反应[7,8,10]。因此，纳米药物在改善治疗选择方面提供了希望。20世纪90年代，第一个聚合物共轭纳米药物SMANCS（苯乙烯马来酸聚合物共轭新制癌素）在日本获得批准，标志着抗癌纳米药物发展的一个重要里程碑[15]。在过去的二十年里，抗癌纳米药物领域经历了巨大的发展和进步[16-18]。许多纳米药物目前正在临床环境中使用，许多其他药物正在进行临床试验（见表1)。 近年来，许多纳米药物被设计和开发用于先进的、侵入性较小的癌症治疗。实例包括基于纳米探针的光动力疗法[12, 19]和硼中子俘获疗法（BNCT）[20, 21]，以及使用磁铁矿的磁热疗[12, 19]，所有这些都显示出有希望的治疗潜力。此外，纳米医学在免疫治疗、基因治疗、预防医学等前沿生物医学领域的应用也取得了重要进展。 表1. 抗癌纳米药物的实例 重要的关注。一个显著的例子是Covid-19的mRNA疫苗的成功，其利用脂质纳米颗粒作为递送系统[22]。在此背景下，本综述探讨了纳米药物在先进癌症治疗和其他生物医学领域的应用前景，如图1所示。 图1. 纳米药物在各种生物医学和治疗领域的新应用 通过对基本思想、当前发展和潜在未来方向的解释，我们强调了纳米医学通过其先进特性的影响，引导我们进入精准医疗和更好的患者结果的新模式。 1.1.纳米药物在光动力疗法中的应用 1.1.1. 纳米设计的光敏剂，一种有前途的癌症治疗方法 尽管肿瘤治疗方法不断扩展，但仍存在重大挑战，包括非特异性、耐药性、低应答率和严重的毒性相关副作用[23]。光动力疗法（PDT）提供了一种非侵入性和靶向性的替代方法，其中光活化的光敏剂（PS）产生活性氧（ROS），导致肿瘤细胞死亡。PDT有望成为解决传统肿瘤治疗策略缺点的有效方法[24]。然而，由于缺乏肿瘤选择性，传统光敏剂的局限性阻碍了PDT的临床转化，导致其在当前临床实践中的应用相对有限[25]。在这方面，纳米光敏剂（NanoPs）的出现是一种克服这些挑战的手段，它利用增强的渗透和滞留（EPR）效应来靶向肿瘤，为增强PDT的功效和特异性提供了巨大的潜力[19]。此外，因为大多数PSS表现出荧光性质，所以可以通过荧光成像，即光动力学诊断（PDD）来区分肿瘤和正常组织。 1.1.2. 用于肿瘤靶向的纳米粒子 与传统的PS相比，纳米SS由于其纳米级尺寸和表面修饰而表现出优越的肿瘤靶向能力[26]。纳米粒子表面可进一步被特异性靶向配体或抗体功能化，使其能够特异性识别和结合肿瘤细胞，从而增强治疗效果并最大限度地减少对正常组织的损伤[26]。通过EPR效应介导的被动积累和使用配体或抗体的主动靶向等策略，纳米粒子可以在肿瘤内精确定位，最大限度地减少脱靶效应并增强治疗效果[27]。此外，纳米材料的光学性质可以通过控制其形态、尺寸和结构来调节，使光敏剂在特定波长下的吸收最大化，从而提高PDT效率并实现更精确的肿瘤治疗[28]。 1.1.3. 光动力疗法的临床应用及纳米材料的应用前景 在过去的二十年里，与PDT相关的临床研究发展迅速，目前已有多个PS被批准用于临床治疗。例如，氨基酮戊酸甲酯（MAL）[29]和5-ALA[30]已被美国食品和药物管理局（FDA）批准分别用于治疗光化性角化病、基底细胞癌（BCC）、浅表性和结节性基底细胞癌以及鳞状细胞癌（SCC）。Radachlorin®还获得了俄罗斯联邦卫生部（MHRF）的批准，用于治疗皮肤癌[31]。欧洲药品管理局（EMA）已批准替莫泊芬用于晚期头颈部鳞状细胞癌的姑息治疗[32]。PDT在皮肤恶性肿瘤，特别是非黑色素瘤皮肤癌如基底细胞癌和鳞状细胞癌的治疗中具有相对成熟的应用基础[33]。其局部治疗方法不仅产生了良好的美容效果，减少了对患者外观的影响，而且还表现出良好的抗肿瘤效果和较低的复发率[34]。在胸部恶性肿瘤领域，PDT作为一种重要的治疗方式，已被批准并广泛应用，尤其是早期非小细胞肺癌[35]。在各种其他领域，如头颈部恶性肿瘤、泌尿生殖系统恶性肿瘤、乳腺恶性肿瘤[36]、颅内恶性肿瘤[37]和胃肠道恶性肿瘤，PDT已显示出广泛的潜力。随着新型纳米光敏剂的合理设计，例如使用超小纳米材料克服血脑挑战，PDT在脑肿瘤治疗中的前景越来越广阔[38]。此外，PDT治疗包括卵巢癌、子宫内膜癌、宫颈癌、骨肉瘤和恶性血液病在内的各种恶性肿瘤的临床研究也在积极进行中。随着研究的不断深入，光动力疗法在临床应用前景广阔。扩大癌症治疗的范围。总之，PDT作为一种局部治疗模式，结合新型光敏剂和纳米技术的发展，有可能为治疗各种恶性肿瘤带来更加个性化和精确的选择，进一步改善治疗结果，提高患者生存率和生活质量。 1.1.4. 利用纳米材料的多功能治疗策略 纳米材料的不断发展赋予了某些类型的纳米材料不仅具有光敏性，还具有声敏性和光热特性[39, 40]。这些特点使PDT能够与声动力疗法（SDT）或光热疗法（PTT）相结合，提供足够的灵活性，与其他治疗模式相结合，以实现协同效应[41, 42]。例如，Liao等人的研究。已经发现二氢卟酚E6表现出有效的光敏性和声敏性，在声动力疗法联合PDT中起着至关重要的作用[43]。此外，利用纳米粒子共同递送化疗药物、免疫调节剂或基因治疗剂能够实现多模式癌症治疗策略[44]。此外，将成像探针集成到纳米系统中可以实时监测治疗反应，促进个性化治疗方法[45]。表2 总结使用纳米粒子的治疗策略和挑战。 表2. 纳米粒的应用及治疗策略 Abbreviations: polymer-modified nanophotosensitizers (PNPSs); metal nanoclusters-based photosensitizers (MNPSs); carbon nanophotosensitizers (CNPSs); quantum dot photosensitizer (QDPSs); upconversion nanoparticles (UCNPs); metal-organic frameworks (MOFs); covalent organic frameworks (COFs); photothermal therapy (PTT); photodynamic diagnosis (PDD). 1.1.5. 挑战与未来展望 纳米材料在癌症治疗中的广泛应用已经取得了长足的进步，不仅在基础研究中，而且在临床研究中都显示出显著的疗效。癌症治疗的疗效与多种因素密切相关，例如纳米粒子本身的特性、其在生物体中的转运过程以及细胞靶标损伤。这些因素包括药物小分子的负载和功能修饰、纳米药物的体内转运和肿瘤积聚、肿瘤内渗透和微环境控制释放以及对肿瘤细胞的特异性损伤和正常组织的生物安全性[68]。然而，尽管取得了重大进展，纳米介导的PDT的广泛临床应用仍然面临着一些挑战。这些挑战包括对生物相容性、长期安全性、合成方法的标准化和监管审批程序的关注。未来的研究方向可能集中于开发多功能纳米粒子平台，完善靶向策略和优化治疗方案，研究药物在体内不同治疗阶段的转运和作用机制，以最大限度地提高治疗效果，同时最大限度地减少不良反应。 总的来说，目前批准用于临床的纳米材料相对较少，大多数仍处于基础研究或临床试验阶段。随着研究的进展，越来越多的临床实验已经开始。可以预见，随着纳米粒子在PDT抗肿瘤治疗基础研究的快速发展，未来将会有更多的相关临床试验，力争将更多的纳米粒子应用于临床。 1.2.纳米药物在免疫治疗中的应用 免疫疗法始于19世纪，当时观察到一些肉瘤患者在化脓性链球菌感染后出现肿瘤消退。这导致使用科利毒素治疗一些肉瘤患者，在一些患者中偶尔出现完全反应[69]。免疫治疗的目的是利用宿主的免疫反应来达到持久的治疗效果。然而，免疫治疗的严重副作用可能诱发自身免疫性和非特异性炎症[70]，目前仍难以控制。 近几十年来，无论是合成的还是天然产生的NPs，由于其独特的物理和化学特性，已成为免疫治疗领域大量研究的主题[71]。通过使用纳米药物和生物材料，有可能将免疫调节剂以靶向方式递送到所需位置，具有许多优点，如改善药代动力学、提高治疗效果和最小化剂量依赖性全身毒性[5,70]。 为了最大限度地发挥免疫治疗药物的效力，应对NP进行适当改造，使其优先从给药部位靶向感兴趣的区域（胃肠外或粘膜疫苗接种途径是常见的给药途径）。下面提到的各种策略正被用于增强纳米药物的免疫原性效果。 1.2.1. 靶向肿瘤免疫微环境 使用改变肿瘤免疫微环境（TIME）的纳米药物是提高抗癌免疫疗法有效性的关键策略[72]。缺氧是由于肿瘤细胞在时间内迅速膨胀，血管扭曲变形所致。这导致免疫抑制细胞的积聚，如调节性T细胞（Tregs）和髓源性抑制细胞（MDSCs），以及免疫抑制因子如转化生长因子β（TGF-β）和血管内皮生长因子（VEGF）的分泌，最近显示其抑制树突状细胞成熟和T细胞浸润。通过关注当时的主要元素，纳米颗粒可能会改变癌细胞周围的免疫抑制环境。此外，增强细胞毒性 T 细胞等效应免疫细胞的浸润、增殖、成熟、存活和/或活化，可通过阻断 TIME 中的免疫抑制，提高免疫疗法的效果[72，73]。Chen等人[74]使用白蛋白包被的MnO2制备pH/H2O2双重响应性纳米颗粒。氧是由MnO2穿透肿瘤时与H2O2和H+反应产生的。通过减少缺氧状态，他们提高了光动力治疗和化疗的有效性。 此外，肿瘤相关巨噬细胞（TAMs）是 TIME 的主要参与者，它们在肿瘤萌发阶段启动抗肿瘤免疫；然而，一旦肿瘤形成，它们就会在肿瘤血管生成、免疫抑制、侵袭和转移中发挥作用。这种差异可能源于巨噬细胞的延展性，导致TAMs从M1极化状态转变为M2极化状态[73, 75]。伦纳德等人使用载有CRISPR复合物的脂质体来沉默哺乳动物雷帕霉素靶蛋白（mTOR）通路，这是一种参与许多重要生理功能（如细胞生长、增殖和自噬）的重要细胞信号通路。这导致巨噬细胞从M2表型极化到M1表型，从而提高化疗的治疗效果[70]。 1.2.2. 靶向和重编程T细胞 T细胞是适应性免疫应答所必需的，并且是淋巴细胞的一部分。免疫介导的细胞死亡是T细胞的作用之一。T细胞可分为两种主要亚型：CD8+和CD4+ T细胞。细胞毒性T细胞，通常称为CD8+ T细胞，特异性破坏癌细胞和病毒感染细胞。相反，CD4+ T细胞通过细胞因子影响其他免疫细胞；或者，通过决定免疫系统是否以及如何对感知到的威胁做出反应，它们间接导致了受感染细胞的死亡。由于T细胞表面含有多种细胞标记，并参与包括癌症在内的多种疾病的免疫应答，因此有多种靶向方法可用于治疗不同的疾病[76]。使用RNA干扰（RNAi）下调特定基因并修饰T细胞活性，对于开发针对多种免疫相关疾病（如癌症、炎症、自身免疫和病毒感染）的定制疗法具有很大的前景。Ramishetti等人描述了一种独特的方法，该方法使用靶向脂质NPs（TLNPs）将siRNA精确递送至小鼠CD4+ T细胞。使用抗CD4单克隆抗体使TLNP表面功能化，允许siRNA仅递送至CD4+ T细胞。TLNPs在体内表现出选择性，只关注原代CD4+T细胞而忽略其他细胞类型。这些TLNP已与几种脂质合成，以增强siRNA递送的稳定性和功效，从而提高其功效[77]。此外，活化的T细胞（ATCs）表达更多的转铁蛋白受体，表明ATCs可以用该技术靶向。所以，谢等人。创建了一种包含转铁蛋白-聚乙烯亚胺（Pei）和siRNA的多聚体作为靶向递送系统，以抑制与炎症ATCs相关的基因。他们还证实了Polyplex治疗哮喘的潜力[76]。 免疫细胞重新编程的劳动密集型过程使Yescarta的CAR-T治疗成本增加到373，000美元，Kymriah的CAR-T治疗成本增加到475，000美元。然而，纳米技术提供了负担得起的纳米载体，可以精确和快速地将肿瘤识别能力编程到宿主T细胞中，从而解决这些问题。它们与靶向淋巴细胞的配体联合使用，将肿瘤特异性CAR货物递送到T细胞中。摄入后，这些NP指导足够量的效应细胞诱导肿瘤消退，其抗癌免疫特性类似于现有的CAR-T技术，通常在体外转导培养的T细胞[78]。 1.2.3. 活化增强NK细胞 先天免疫系统的第一道防线由自然杀伤（NK）细胞组成，NK细胞对于识别癌细胞和抵御病毒感染至关重要。NK细胞占人类外周血中所有淋巴细胞的5%至20%[79]。尽管基于NK细胞的免疫疗法非常有前景，但它仍然遇到了一些重大障碍，如NK细胞增殖有限和体内寿命短，以及昂贵的治疗费用和复杂的输送系统[80]。然而，基于NP的疗法试图通过选择性激活NK细胞来克服这些障碍。根据Chandrasekaran等人[81]，通过与肿瘤引流淋巴结（TDLN）内的NK细胞偶联的TRAIL修饰的脂质体抑制小鼠的皮下肿瘤转移。此外，他们发现用TRAIL功能化的NK细胞延长了其在TDLN中的滞留时间，从而导致肿瘤细胞发生凋亡。后来，Gao等人[82]创建了具有二硒醚修饰的RGD肽的聚合NP，其靶向肿瘤，允许用于肿瘤积聚的全身注射和用于NK细胞介导的癌症免疫疗法的辐射暴露。基于给药方式，碳纳米管（CNT）也可能具有免疫抑制作用。在C57BL/6成年小鼠中，吸入CNT导致T细胞增殖减少，NK细胞活性降低，脾脏中IL-10（一种抗炎细胞因子）的基因产生增加。这导致了小鼠的系统性免疫抑制。此外，与感染呼吸道合胞病毒的小鼠相比，鼻内给予金纳米棒可减少TNF-α、GM-CSF、IL-17和IL-12p70，并增加IL-9[83]。在另一项研究中，使用双特异性抗体（SS-FC、抗CD16和抗CEA）包被钌NPs，刺激NK细胞引起坏死和凋亡，进而进一步激活免疫反应[84]。 1.2.4. 激活NKG2D受体 NKG2D是一种类似于C型凝集素的活化受体，广泛表达于CD8+ T、γδT、NK和NKT细胞。小鼠UL-16结合蛋白（ULBP）样转录物1、H60和维甲酸早期诱导转录物-1（Rae-1）是NKG2D配体。由于大多数正常组织缺乏被病毒感染或肿瘤细胞强迫表达的NKG2D配体，这些配体在免疫治疗中作为肿瘤靶向抗原发挥作用[85]。TGF-β抑制剂和硒代半胱氨酸纳米乳通过增敏NKG2D配体增强NK细胞的裂解能力。TGF-β抑制剂成功阻断TGF-β/TGF-βRI/Smad2/3信号通路，导致肿瘤细胞表面NKG2D配体数量增加。在γδT淋巴细胞中，硒半胱氨酸抑制PD-1表达，同时促进NKG2D受体的产生[84]。另一项研究表明，包被有小鼠和人片段可结晶（FC）-融合NKG2D（FC-NKG2D）的NKG2D/NPs可以通过剂量依赖性磁细胞分选，在体外靶向多种NKG2D配体阳性肿瘤类型。NKG2D/NPs可以靶向多种肿瘤类型，并且肿瘤靶向氧化铁NPs（IONP）研究的概念验证阶段可以通过磁分离平台进行辅助[86]。 1.2.5. 靶向抗原呈递细胞 巨噬细胞、树突状细胞（DC）和B淋巴细胞是抗原呈递细胞（APC）的例子，它们是先天免疫系统的组成部分，并且对于启动和控制适应性应答是至关重要的。其主要职责是识别、捕获和消化抗原。在过去的20年里，抗原靶向策略作为传染病、自身免疫和癌症的预防和治疗措施得到了广泛的研究。这些策略旨在通过抗原捕获机制提高疫苗效率[87]。NPS表面的抗原呈递类似于病毒呈递抗原的自然方式，通过控制和延迟抗原的释放，NPS可以调节免疫系统对其的暴露。此外，同时加载抗原和佐剂可以通过NPs提高大多数蛋白质的限制性免疫原性。在这方面，聚合物NP在已引入用于负载和抗原递送的各种纳米载体中引起了关注。已经检测了各种类型的聚合物，例如聚酯、聚（α-羟基酸）、蛋白质和多糖。明胶具有最小的免疫原性，也是一种很好的疫苗纳米载体。在这方面，卵清蛋白（OVA）和破伤风类毒素等抗原被固定在明胶 NPs（GNPs）表面，通过改变抗原的负载方法和 NPs 的表面特性，可以操纵对抗原的免疫反应[88]。此外，通常将PEG添加到NPs中以减少其与网状内皮系统的相互作用[89]。 1.2.6. 作为免疫检查点抑制剂的载体 免疫细胞的表面蛋白被称为免疫检查点，其功能是通过多种抗原对免疫系统的激活进行负调节。免疫检查点分子在肿瘤细胞和免疫细胞上广泛表达[5,90]。然而，缺乏理想的免疫治疗方法（IMT）、免疫相关不良事件（IRAEs）和低应答率限制了使用创新免疫检查点抑制剂（ICIs）进行联合治疗的研究。核动力源已成为促进跨学科合作的有效工具。通过NPS有针对性地提供ICIS既可行又有效；它消除了主要障碍，提高了治疗效果，并证明了进一步临床研究的合理性[90]。基于脂质的NPs（脂质体和LNPs）在临床试验中越来越多地用于递送RNA和免疫治疗药物，但其在ICIS中的应用并没有跟上需求[90]。 1.2.7. 纳米免疫治疗的临床进展 基于迄今为止取得的进展，纳米免疫疗法在治疗各种疾病方面显示出了良好的前景。这些结果中的大多数仍处于临床前阶段，其中一些已获得FDA批准，目前正在进行临床试验，如表3所示。脂质体、聚合物NPs和PEG-药物结合物目前被批准用于治疗各种免疫疾病[91]。 表3. 目前正在进行免疫治疗临床试验的纳米粒的详细信息 1/2/3期临床试验已经评估了ALT-803（靶向NK和T细胞的重组IL-15超激动剂复合物纳米凝胶）用于治疗白血病或晚期实体瘤（例如NSCLC、黑色素瘤、肾癌、结肠癌和乳腺癌）患者的安全性和有效性。LNP-mRNA技术是目前正在进行临床研究的首选纳米制剂[92]，其脂质体复合物允许将治疗性mRNA癌症疫苗靶向递送至淋巴器官中的APC。Nanobiotix创造了Hensify®，以增强局部免疫系统并从物理上杀死恶性肿瘤。Nanobiotix正在进行多项临床试验，并已获得美国FDA批准，开始使用PD-1和NBTXR3抗体治疗肺癌的联合试验[5]。截至2023年，抗PD-1/PD-L1和放射治疗以及NBTXR3正在进行1期和2期临床试验，以帮助治疗晚期实体恶性肿瘤患者（NCT05039632））。此外，正在进行一项新型RNA-纳米颗粒疫苗的临床试验，用于治疗辅助抗PD-1抗体治疗后的早期黑色素瘤复发，以评估肿瘤特异性RNA-NP疫苗接种在接受辅助抗PD1（A-PD1）治疗的IIB-IV期黑色素瘤患者中的安全性和生存能力（NCT05264974）。 III期临床试验正在评估Tecemotide，一种MUC1特异性癌症免疫疗法，用于治疗IIIA/IIIB期NSCLC。一种名为Lipovaxin-MM的树突状细胞靶向脂质体疫苗也开始了恶性黑色素瘤的1期临床试验。基于环糊精聚合物纳米颗粒（CDP）技术，CRLX101是一流的纳米药物，具有将治疗转化为积极临床结果的潜力[93]。 1.2.8. 挑战和前景 尽管人们对基于NP的免疫疗法越来越感兴趣，但这些免疫刺激性NP的临床转化仍然存在重大问题。在评估NPs的毒性时，重要的是要考虑这样一个事实，即它们中的一些可能会改变细胞内的信号通路。当NP与血清蛋白相互作用时，免疫系统可以将它们识别为外来物质，并产生针对它们的自身免疫反应。因此，为了在临床环境中成功使用NP，必须将其设计为能够防止ROS、超敏反应或过敏性致敏的产生，并易于从体内清除[101]。采用的主要障碍是对纳米颗粒与生物分子的作用模式的理解不足。这导致一些纳米制剂退出市场，甚至在获得FDA批准后也是如此。其中的一些例子包括Feridex I.V.（Endorem，Ferumoxides）、Lumirem（Gastromark）、Resovist（Cliavist）、Sinerem（Combidex）和Clariscan（PEG-Fero，Feruglose NC100150）[93]。 参考文献 1. Glob. Health J. 2023, 7, 70–77. 2. Ther. Deliv. 2018, 9, 409–412. 3. Biophys. Rev. 2017, 9, 79–89. 4. Biomater. Res. 2018, 22, 24. 5. Cancers 2020, 12, 3773.  6. Cancer Res. 1986, 46, 6387–6392.  7. Adv. Drug Deliv. Rev. 2020, 157, 142–160.  8. Expert Opin. Drug Deliv. 2022, 19, 199–212.  9. Bioconjugate Chem. 2010, 21, 797–802.  10. Adv. Drug Deliv. Rev. 2015, 91, 3–6. 11. Adv. Drug Deliv. Rev. 2013, 65, 71–79.  12. Microcirculation 2016, 23, 173–182.  13. Nano Today 2020, 35, 100970.  14. Clin. Cancer Res. 2017, 23, 4190–4202.  15. J. Control. Release 2001, 74, 47–61.  16. J. Control. Release 2020, 326, 164–171. 17. Nano Today 2020, 31, 100853.  18. Drug Deliv. Transl. Res. 2020, 10, 726–729.  19. Photodiagnosis Photodyn. Ther. 2021, 36, 102597.  20. Biomaterials 2021, 269, 120631.  21. Biomaterials 2021, 268, 120551. 22. Chem. Eng. News 2021, 99, 144. 23. Cancer Discov. 2019, 9, 1167–1181.  24. Acta Pharm. Sin. B 2018, 8, 137–146.  25. Cancers 2020, 12, 2793. 26. Chem. Rev. 2021, 121, 13454–13619.  27. Nanomedicine 2023, 48, 102636. 28. Mikrochim. Acta 2022, 189, 120.  29. JAMA Dermatol. 2017, 153, 289–295.  30. Braz. J. Med. Biol. Res. 2020, 53, e8457.  31. Br. J. Cancer 2020, 123, 871–873.  32. Laryngoscope 2018, 128, 657–663. 33. Ther. Clin. Risk Manag. 2008, 4, 1–9. 34. Int. J. Mol. Sci. 2020, 21, 3327.  35. Ther. 2021, 33, 102203.  36. Breast 2017, 31, 105–113.  37. Mol. Pharm. 2022, 19, 1927–1951. 38. Biomedicines 2022, 10, 96. 39. ACS Appl. Mater. Interfaces 2020, 12, 40728–40739. 40. Pharmaceutics 2023, 7, 2293.  41. J. Control. Release 2023, 362, 425–445.  42. ACS Nano 2015, 24, 2904–2916.  43. Mol. Pharm. 2023, 20, 875–885.  44. J. Biomed. Nanotechnol. 2022, 18, 837–848. 45. Nanoscale Res. Lett. 2018, 13, 10.  46. Adv. Funct. Mater. 2019, 29, 1905013.  47. Carbohydr. Polym. 2020, 229, 115394.  48. ACS Appl. Mater. Interfaces 2020, 12, 12591–12599. 49. J. Mater. Chem. B 2021, 9, 2042–2053.  50. J. Am. Chem. Soc. 2012, 134, 17862–17865.  51. Int. J. Pharm. 2016, 498, 335–346. 52. ACS Appl. Mater. Interfaces 2018, 10, 14438–14446.  53. Part. Part. Syst. Charact. 2017, 34, 1600413. 54. ACS Appl. Mater. Interfaces 2020, 12, 12549–12556.  55. Small 2017, 13, 1603459.  56. Angew. Chem. Int. Ed. Engl. 2019, 58, 14213–14218.  57. J. Control Release 2006, 114, 343–347. 58. Nanomedicine 2010, 5, 1161–1171. 59. Int. J. Pharm. 2019, 554, 256–263.  60. Anal. Chem. 2020, 92, 15169–15178. 61. Nano Converg. 2020, 7, 10. 62. RSC Adv. 2020, 10, 22091–22101.  63. ACS Nano 2011, 27, 7000–7009.  64. J. Mater. Chem. B 2013, 1, 4972–4982.  65. J. Biomed. Opt. 2009, 14, 021009. 66. Angew. Chem. Int. Ed. Engl. 2015, 54, 11526–11530.  67. Int. J. Mol. Sci. 2021, 10, 9779.  68. Chem. Asian J. 2018, 13, 3122–3149. 69. Am. Soc. Clin. Oncol. Educ. Book 2016, 36, 298–308.  70. Cancer Gene Ther. 2021, 28, 911–923.  71. Drug Discov. Today 2024, 29, 103905. 72. Acc. Chem. Res. 2019, 52, 1543–1554.  73. Bioact. Mater. 2021, 6, 1973–1987. 74. Adv. Mater. 2016, 28, 7129–7136.  75. Front. Immunol. 2023, 14, 1295257.  76. Biomater. Res. 2021, 25, 44.  77. ACS Nano 2015, 9, 6706–6716.  78. Acta Biomater. 2020, 109, 21–36. 79. Cells 2021, 10, 1420.  80. Front. Chem. 2020, 8, 597806.  81. Biomaterials 2016, 77, 66–76.  82. Adv. Mater. 2020, 32, 1907568. 83. Biomater. Adv. 2022, 135, 212726.  84. Cancers 2022, 14, 5438.  85. Int. J. Nanomed. 2017, 12, 3095–3107. 86. Nanotechnology 2014, 25, 475101.  87. Front. Immunol. 2023, 14, 1080238. 88. Int. J. Pharm. 2021, 593, 120123.  89. Front. Mol. Biosci. 2020, 7, 193. 90. J. Nanobiotechnology 2023, 21, 339.  91. Acta Pharm. Sin. B 2022, 12, 3028–3048. 92. Adv. Sci. 2022, 9, 2204335.  93. Int. J. Mol. Sci. 2022, 23, 1685. 94. Cells 2021, 10, 2831.  95. Pharmaceutics 2022, 14, 1722.  96. J. Control. Release 2021, 330, 1016–1033.  97. Oncotarget 2016, 7, 42408–42421. 98. PLoS ONE 2015, 10, e0139785.  99. J. ImmunoTherapy Cancer 2023, 11 (Suppl. 1), A867–A869. 100. J. Immunother. 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