Cisplatin

• Cash runway extended into the second half of 2026 • Average sales price per share was over 10% higher than the June 2025 public offering price SHELTON, Conn., Aug. 4, 2025 /PRNewswire/ -- Intensity Therapeutics, Inc. (Nasdaq: INTS) ("Intensity" or "the Company"), a late-stage clinical biotechnology company focused on the discovery and development of novel intratumoral cancer therapies that are designed to kill tumors and increase immune system recognition of cancers using its proprietary non-covalent conjugation technology, announces that in July 2025 the Company added $6.6 million in gross proceeds ($6.3 million net) by selling 19,868,658 shares of its common stock via its At-the-Market offering (the "ATM") at an average price of $0.3323 per share. Following such sales of common stock pursuant to the ATM, the Company has 46,035,081 shares of common stock issued and outstanding as of July 31, 2025. "We were able to take advantage of strong liquidity and favorable prices in our stock last month. The proceeds from these ATM sales strengthen our balance sheet considerably and allow us to continue to advance the clinical trials into the second half of 2026," said Lewis H. Bender, President and CEO of Intensity. "We are also pleased to announce that the average price per share for these ATM sales was more than 10% higher than our recently completed June 2025 public offering, and the costs to raise this incremental capital were much lower. We will continue to be selective and strategic in the deployment of the remainder of the ATM." About At the Market Transactions "At-the-Market" (ATM) offerings, also known as "ATM" programs, refer to a method where a public company sells its newly issued shares directly into the existing trading market at the prevailing market price, rather than through a traditional underwritten offering. This approach allows companies to raise capital opportunistically and incrementally, as needed, with minimal disruption to the market and typically lower costs. About INT230-6 INT230-6, Intensity's lead proprietary investigational product candidate, is designed for direct intratumoral injection. INT230-6 was discovered using Intensity's proprietary DfuseRx℠ technology platform. The drug consists of two proven, potent anti-cancer agents, cisplatin and vinblastine sulfate, and a diffusion and cell penetration enhancer molecule ("SHAO") that facilitates the dispersion of potent cytotoxic drugs throughout tumors, allowing the active agents to diffuse into cancer cells. These agents remain in the tumor, resulting in a favorable safety profile. In addition to local disease control and direct tumor killing, INT230-6 causes a release of a bolus of neoantigens specific to the malignancy, leading to immune system engagement and systemic anti-tumor effects. Importantly, these effects are mediated without immunosuppression, which often occurs with systemic chemotherapy. About Intensity Therapeutics Intensity is a late-stage clinical biotechnology company whose novel engineered chemistry enables aqueous cytotoxic-containing drug formulations to mix and saturate a tumor's dense, high-fat, pressurized environment following direct intratumoral injection. As a result of the saturation, Intensity's clinical trials have demonstrated the ability of INT230-6 to kill tumors and elicit an adaptive immune response within days of injection, representing a new approach to cancer cell death that holds the potential to shift the treatment paradigm and turn many deadly cancers into chronic diseases even for malignancies that do not respond to conventional immunotherapy. Intensity has completed two clinical studies and enrolled over 200 patients using INT230-6: a Phase 1/2 dose escalation study in metastatic cancers including sarcomas (NCT03058289), and a Phase 2 randomized control clinical trial in locally advanced breast cancer (the "INVINCIBLE-2 Study") (NCT04781725) in women without undergoing chemotherapy prior to their surgery. The Company initiated a Phase 3 trial in soft tissue sarcoma (the "INVINCIBLE-3 Study") (NCT06263231), testing INT230-6 as second or third-line monotherapy compared to the standard of care ("SOC") with overall survival as an endpoint. Intensity also initiated a Phase 2 study (the "INVINCIBLE-4 Study") (NCT06358573) in collaboration with the Swiss Cancer Group, formerly the Swiss Group for Clinical Cancer Research, SAKK, as part of a Phase 2/3 program evaluating INT230-6 followed by the SOC immunochemotherapy and the SOC alone for patients with presurgical triple-negative breast cancer. Pathological complete response ("pCR") is the endpoint. For more information about Intensity, including publications, papers, and posters about its novel approach to cancer therapeutics, visit www.intensitytherapeutics.com. Forward-Looking Statements Certain statements in this press release may constitute "forward-looking statements" within the meaning of the United States Private Securities Litigation Reform Act of 1995, as amended to date. These statements include, but are not limited to, statements relating to the Company's expected future plans, cash runway, development activities, projected milestones, business activities or results. When or if used in this communication, the words "may," "could," "should," "anticipate," "believe," "estimate," "expect," "intend," "plan," "predict" and similar expressions and their variants, as they relate to the Company or its management, may identify forward-looking statements. The forward-looking statements contained in this press release are based on management's current expectations and projections about future events. Nevertheless, actual results or events could differ materially from the plans, intentions, and expectations disclosed in, or implied by, the forward-looking statements. These risks and uncertainties, many of which are beyond our control, include: the initiation, timing, progress and results of future preclinical studies and clinical trials and research and development programs; the need to raise additional funding before the Company can expect to generate any revenues from product sales; plans to develop and commercialize product candidates; the timing or likelihood of regulatory filings and approvals; the ability of the Company's research to generate and advance additional product candidates; the risk that product candidates that appear promising in early research and clinical trials do not demonstrate safety and/or efficacy in larger-scale or later clinical trials; the implementation of the Company's business model, strategic plans for the Company's business, product candidates and technology; commercialization, marketing and manufacturing capabilities and strategy; the rate and degree of market acceptance and clinical utility of the Company's system; the Company's competitive position; the Company's intellectual property position; developments and projections relating to the Company's competitors and its industry; the Company's ability to maintain and establish collaborations or obtain additional funding; expectations related to the use of cash and cash equivalents and investments; our potential inability to satisfy the Nasdaq Capital Market's requirements for continued listing and be subject to delisting; estimates regarding expenses, future revenue, capital requirements and needs for additional financing; and other risks described in the section entitled "Risk Factors" in the Company's Annual Report on Form 10-K for the year ended December 31, 2024 and in the Company's subsequent SEC filings, which can be obtained on the SEC website at www.sec.gov. Readers are cautioned not to place undue reliance on the forward-looking statements, which speak only as of the date on which they are made and reflect management's current estimates, projections, expectations and beliefs. The Company does not plan to update any such forward-looking statements and expressly disclaims any duty to update the information contained in this press release except as required by law. Investor Relations Contact: Justin Kulik Justin@coreir.com CORE IR (516) 222-2560 Media Contact: Jules Abraham CORE IR pr@coreir.com View original content to download multimedia:https://www.prnewswire.com/news-releases/intensity-therapeutics-inc-raises-6-6-million-from-at-the-market-offering-atm-stock-sales-in-july-2025--302520138.html SOURCE Intensity Therapeutics Inc.

摘要近年来，我国儿童常见病发病率逐渐上升且低龄化日益显著。作为特殊人群，儿童用药与成人相比，除具有同适应证用药不同、剂量不同、辅料不同等特点以外，用药依从性差是影响其临床疗效的重要因素。与普通注射剂相比，儿童用长效注射剂可降低药物突释带来的副作用，并可大幅度减少注射次数，从而显著提高儿童患者依从性，提高临床疗效。长效注射剂应用于儿科具有显著优势。该文以药物和材料相互作用分类，综述儿童用长效注射剂研究进展，可为儿童用长效注射剂开发提供参考。_正文_我国儿童疾病如发育迟缓、哮喘、艾滋病、糖尿病、癌症等的发病率逐渐上升且低龄化趋势日益显著。2020年我国儿童人口占总人口的17.95%，儿童医药市场在总医药市场中所占份额却不到5%[1]，这远不能满足我国庞大的儿童用药需求。儿童作为特殊人群，其用药与成人相比，除具有同适应证用药不同、剂量不同、辅料不同等特点外，用药依从性差是影响临床疗效的重要因素[2]。长效注射剂是指通过单次注射给药，实现较长时间维持相对稳定血药浓度，从而起到缓释或控释作用的制剂[3]。与普通注射剂相比，应用于儿童的长效注射剂，可降低因药物突释带来的副作用，并可大幅度减少注射次数，显著提高患者依从性和临床疗效[4]。长效注射剂应用于儿童疾病方面具有显著优势。常用的药物长效递送技术有化学偶联、融合蛋白、单克隆抗体、微球、纳米晶、水凝胶等，见图1。本文按药物和材料相互作用进行分类，对儿童用长效注射剂的基础研究进展进行综述。图1 儿童用长效注射剂递送技术Fig.1 Long-acting injectable delivery techniques for children1化学偶联1.1 聚乙二醇(polyethylene glycol，PEG)修饰PEG修饰可通过降低肾脏过滤速度、减少蛋白酶降解和更好地模拟人体激素分泌特点，延长药物在体内的循环时间。PEG修饰制剂稳定性好，可提高药物生物相容性[5]。生长激素是儿童生长激素缺乏症(growth hormone deficiency，GHD)的主要治疗药物，需要每天注射。JINTROLONG(金赛增@)是一种PEG长效重组人生长激素(recombinant human growth hormone，rhGH)，由40kDa的PEG残基连接到rhGH上，使其具备长效缓释效果[6]。儿童Ⅲ期临床试验显示，与每天给予rhGH相比，每周使用JINTROLONG(金赛增@)身高增长速度更快，疗效和安全性相同[7]。非格司亭被广泛应用于预防实体癌或血液系统癌症化学治疗(化疗)所致中性粒细胞减少。曲培非格司亭和利培非格司亭是分别连接23kDa和20kDa分子量PEG的新型PEG化非格司亭。LEE等[8]和BELOGUROVA等[9]在临床评估试验中得出结论，曲培非格司亭终末半衰期>40h，利培非格司亭单次注射后药物滞留时间最长可达110h。二者对儿童具有较高的安全性，可提高儿童患者用药依从性，缩短住院时间。1.2 暂时连接(transient conjugation，TransCon)技术TransCon技术是指将药物通过连接子可逆地结合到长效载体形成前药，达到长效目的的技术。该前药在体内可以缓慢释放出活性药物，从而实现长效作用。软骨发育不全(achondroplasis，ACH)是一种最常见遗传性侏儒症，在新生儿中发病率为1/15000~1/77000。C型利钠肽(C-type natriuretic peptide，CNP)能从根源上治疗该病。人体天然CNP半衰期短，仅有2~3min，需要连续静脉输注使用，难以临床应用[10]。TransCon CNP和Lonapegsomatropin是2种通过TransCon技术得到的儿童用长效注射剂。TransCon CNP是一种新型CNP前药，通过可裂解接头偶联到PEG载体分子上，用于治疗儿童ACH。Lonapegsomatropin则是将rhGH由特定链接键链接到惰性甲氧基PEG载体上，用于治疗GHD。BREINHOLT等[11]证实，TransCon CNP在小鼠和非人灵长类动物模型中，半衰期长达120h，可每周给药1次缓慢释放药物。目前TransCon CNP在中国与全球其他地区同步开展Ⅱ期临床试验[12-13]。与rhGH半衰期约3h相比，Lonapegsomatropin半衰期约为25h[14]。美国食品药品管理局(Food and Drug Administration，FDA)于2021年秋季批准了Lonapegsomatropin，每周1次用于治疗体质量≥11.5kg、因内源性生长激素分泌不足导致生长缓慢的≥1岁儿童[15]。1.3 非共价结合白蛋白机制是将具有非共价白蛋白结合特性的脂肪酸与药物结合，来结合内源性白蛋白，从而延长药物半衰期[16]。德谷胰岛素由在地特胰岛素B链29号位点的赖氨酸上连接一个16碳脂肪二酸侧链得到，进入血液循环后，可与白蛋白可逆性结合，蛋白结合率>99%，进一步延缓到达靶组织的时间[17]。德谷胰岛素作用持续时间>42h，有望成为第3个被批准在中国上市的儿童长效胰岛素。Somapacitan是一种长效hGH类似物，该药将非共价白蛋白结合特性的脂肪酸通过烷基化与人生长激素结合，可每周给药1次[18]。2023年4月FDA扩大了Somapacitan适应证，批准其用于治疗≥2.5岁儿童GHD。1.4 化学修饰通过对药物进行酯化、制成难溶性盐、改变药物可溶pH值均可延长药物半衰期，形成长效注射药物。化学修饰策略可在最大限度不影响药物生物活性的情况下延长半衰期。有研究将抗精神病药物帕利哌酮酯化形成帕利培酮棕榈酸酯，肌内注射后缓慢地溶解为棕榈酸与帕利哌酮发挥药效，可实现6个月给药1次[19]。PETRIC等[20]的临床试验表明，帕利培酮棕榈酸酯在青少年患者中安全有效，且在临床效果、副作用和住院治疗方面都优于利培酮。苄星青霉素是青霉素的二苄基乙二胺盐，在注射部位缓慢释放并水解为青霉素，有效血药浓度可维持2~4周，用于预防儿童风湿热复发和控制链球菌感染流行[21]。甘精胰岛素是将人胰岛素A链21号位点的门冬氨酸替换成甘氨酸，在B链加上2个精氨酸残基得到的长效胰岛素，可溶性pH值变为4.0，皮下注射到中性pH条件后，形成细小沉淀[22]。这些微沉淀在较长时间里持续释放胰岛素单体，作用可持续30h，从而达到长效降糖效果。2物理亲和2.1 纳米晶纳米晶注射混悬剂利用难溶药物释放速度慢的机制，经皮下或深部肌内注射后可缓慢持续释放药物进入血液或淋巴循环，从而可形成长效注射剂。纳米晶可以解决微球载药量小的问题。2021年，有16万例儿童新发人类免疫缺陷病毒(human immunodeficiency virus，HIV)感染，占全部感染者总数的4%，但是却占到因该疾病死亡人数的15%[23]。长效注射剂在儿童各个年龄段预防和治疗HIV感染方面具有很大潜力[24]。卡博特韦/利匹韦林(cabotegravir/rilpivirine，Cabenuva)是针对HIV的首个长效注射疗法，是使用纳米晶技术制备的注射混悬剂。LOWENTHAL等[25]的临床研究发现，青少年注射卡博特韦或者利匹韦林具有高度接受和耐受性，有可能成为青少年HIV感染者的第一选择。2.2 微球微球具有良好的生物相容性，可通过结构修饰来调节药物释放动力学[26]，其通过皮下或肌内注射等方式进入人体后，聚合物材料在生理环境下会逐渐溶蚀降解，从而达到长效缓释效果。曲普瑞林微球和醋酸亮丙瑞林微球长效剂型在儿童中枢性性早熟(central precocious puberty，CPP)治疗中优势显著[27-29]。2024年7月9日，注射用双羟萘酸曲普瑞林微球的每6个月注射1次的剂型经中国国家药品监督管理局正式批准用于CPP的治疗，该药进一步延长了注射间隔，提高了儿童患者依从性。此外，市场上已有多种用于治疗儿童疾病的长效微球制剂。如用于治疗儿童2型糖尿病的艾塞那肽聚乳酸-羟基乙酸共聚物[poly(lactic-coglycolic acid)，PLGA]微球[30]，以及用于治疗儿童激素分泌过多的生长抑素长效制剂奥曲肽PLGA微球、兰瑞肽微球[31]以及用于GHD的微球制剂LB03002。相关临床试验表明，奥曲肽PLGA微球可实现每个月注射1次[32]，而每周注射1次0.5mg·kg-1LB03002与连续7d每天注射1次0.21mg·kg-1rhGH具有等同疗效[33]。但微球也存在一些问题，如突释现象、容易引发感染、蛋白质降解以及难以大规模生产等。DIANA等[34]将GH制成葡聚糖颗粒，并通过自组装封装到PLGA微球。葡聚糖可调节渗透压减少突释。相关药动学研究表明，该制剂表现出较小的早期突释，且可持续释放30d。该微球给药系统可能成为未来应用于临床的rhGH长效注射剂。2.3 聚合物纳米粒药物被包裹在聚合物基质中形成聚合物纳米粒，聚合物可以延缓药物降解，从而延长药物递送时间。眼外伤和随后的纤维变性视网膜并发症是造成儿童和年轻人失明的主要原因。UEDA等[35]建立了模拟挫伤和穿透伤的猪眼外伤模型，并在玻璃体内注射包载达沙替尼(dasatinib，Das)的PLGA纳米粒(Das-PLGA)注射液。结果表明，Das-PLGA可持续释放达沙替尼12d，显著减少早期纤维化视网膜变化。疫苗是预防传染类疾病和死亡的重要制剂，但许多疫苗必须注射多次才能起效，如疟疾疫苗。KANG等[36]合成了三甲基壳聚糖纳米粒，电荷表面可以负载不同阶段抗原，选用透明质酸盐作为表面保护涂层，防止外层蛋白质立即释放和降解，将抗原的释放时间控制在几天到几个月，达到持久产生保护性免疫反应的目的。与传统疟疾疫苗相比，2次注射间隔可长达4周。开发此类疫苗对于在儿童中减少疟疾这一类致命病毒至关重要。2.4 脂质体多囊脂质体通过外层囊泡的逐渐降解实现药物的持续释放。布比卡因是临床常用局部麻醉镇痛剂，其普通注射剂不能满足儿童术后长时间镇痛需要，因此需要具有长效缓释作用的注射剂。布比卡因多囊脂质体镇痛时间长达72h，可满足手术疼痛控制时间。目前脂质体布比卡因适用于多种儿童术后疼痛控制[37-38]，具有良好安全性和疗效。2.5 包合物奈韦拉平(nevirapine，NVP)作为抗逆转录病毒治疗药物，可阻断HIV母婴传播。YANG等[39]开发了NVP长效注射形式，将NVP与聚己内酯(polycaprolactone，PCL)制备成结晶包合物。与纯NVP晶体相比，NVP-PCL包合物晶体溶解度降低至原来的1/4，溶解速度减慢，并在体温下pH值7.4的PBS溶液中稳定至少6周，表现为较强的缓释特性。2.6 水凝胶水凝胶多孔结构和水溶性有利于药物负载，药物释放取决于水凝胶溶胀和药物从聚合物中的扩散，因局部持续药物释放而被广泛用作长效制剂。2.6.1 整体水凝胶梗阻性肾病是儿童肾脏疾病的主要原因，可通过局部和持续输送白细胞介素-10(interleukin10，IL-10)和抗转化生长因子β(anti transforming growth factor-β，anti-TGF-β)治疗。RODELL等[40]设计可注射透明质酸水凝胶，将IL-10、anti-TGF-β结合在一起，降解试验表明，其体外释放时间长达3周，为梗阻性肾病的治疗提供了新的长效治疗策略。视网膜母细胞瘤是儿童最常见的原发性眼恶性肿瘤，HUO等[41]和TAICH等[42]制备了负载拓扑替康(topotecan，TPT)的聚己内酯-PEG-聚己内酯(PCL PEG-PCL)嵌段共聚物水凝胶以及温度敏感水凝胶。前者体外释放曲线显示TPT从嵌段共聚物水凝胶持续释放长达7d。后者在接近体温时，可在视网膜母细胞瘤肿瘤组织中缓慢释放TPT，持续释放>400h。二者在未来转化为临床将具有延长治疗效果、降低患者玻璃体注射频次的优势，有望成为眼内视网膜母细胞瘤治疗的新策略。同样，温度敏感水凝胶在骨肉瘤(osteosarcoma，OS)中也有所应用。OS是一种严重的原发性骨恶性肿瘤，患者多为儿童和青少年。SI等[43]和SHAN等[44]分别制备了包载多柔比星和顺铂的PLGA-PEG PLGA三嵌段共聚物水凝胶和包载甲氨蝶呤和阿伦磷酸钠的聚(L-缬氨酸)(poly-L-valine，PLV)水凝胶。2种水凝胶可在适当温度下经历溶胶-凝胶转变持续释放药物。体外释放结果显示，PLGA-PEG-PLGA共聚物可实现10d持续释放多柔比星和顺铂。PLV水凝胶在第1周内小部分降解，第2周水凝胶体积减少到50%，4周后水凝胶降解完全，也呈现出缓释特点。二者在OS治疗中具有潜在应用价值。2.6.2 水凝胶-微球较大的水凝胶微球粒径相较于较小的水凝胶微球粒径具有更长药物释放时间，且药物与水凝胶之间分子相互作用可以延缓药物从水凝胶微球中释放。万古霉素是治疗儿童慢性骨髓炎的“最后一线药物”，需要长期、大剂量给药，这可能导致耐药性、肾毒性等多种副作用。ZHANG等[45]以丝素蛋白为药物载体，装载万古霉素形成药物微球，然后使用丝素蛋白纳米纤维溶液制备可注射水凝胶作为药物的载体。万古霉素从水凝胶中持续释放达25d，且对大肠埃希菌和金黄色葡萄球菌均有较强抗菌活性，抗菌时间长达10d。此外，QIANG等[46]进一步开发了一种载有血管内皮生长因子、胰岛素样生长因子-1(insulin like growth factor-1，IGF-1)和贝伐单抗的内外双层PLGA微球水凝胶制剂，用于促进儿童受伤后软骨分化和再生以及抑制骨桥形成。体外释放试验表明，约80%贝伐单抗在第1周被释放，而只有少量IGF-1被释放。在接下来的2周内，IGF-1释放量稳步增加，该制剂表现出良好的缓释特性。同样机制的有长春新碱葡聚糖微球与壳聚糖-β-甘油磷酸凝胶协同疗法制剂[47]。该制剂可克服硫酸长春新碱血清半衰期短(12min)，给药频率高(每平方米体表面积1.4mg，每周注射1次，连续4周)和广泛的蛋白质结合的缺点。制剂包载的药物释放维持长达30d，在治疗儿童急性淋巴细胞白血病、霍奇金淋巴瘤等实体瘤方面具有更广阔前景。3生物相互作用3.1 融合蛋白融合蛋白是指利用基因工程等技术将某种具有生物学活性的功能蛋白分子与其他天然蛋白(融合伴侣)融合产生的新型蛋白[48]。融合蛋白技术依靠融合伴侣的长效机制和增加分子大小来延长半衰期。根据融合伴侣不同，融合蛋白分为可结晶片段(fragment crystallizable，Fc)融合蛋白、白蛋白融合蛋白、C-末端肽(C-Terminal peptide，CTP)融合蛋白等。融合蛋白类药物的融合伴侣结构简单，具有免疫原性低、变态反应少的特点。Fc结构域可增大药物分子量，减少肾脏排泄，并且因其新生Fc受体具有再循环的能力从而延长药物血液循环时间。SHAPIRO[49]进行的临床研究表明，将重组凝血因子Ⅷ或IX与Fc融合以治疗儿童血友病，可实现每周注射1次。Rilonacept由人IL-1受体胞外区与人免疫球蛋白G1(immunoglobulin G1，IgG1)的Fc段融合而成，其半衰期可达8d[50]。FDA批准其用于治疗≥12岁儿童复发性心包炎和冷吡啉相关周期性综合征。还有学者使用可延长半衰期的白蛋白连接凝血因子Ⅸ形成重组融合蛋白(rIX-FP)，后者较rFIX药动学特征改善，半衰期延长约5倍[51]。Somatrogon(MOD-4023)是一种利用人绒毛膜促性腺激素β亚基羧基末端肽修饰的长效hGH，该肽可保护蛋白质免受蛋白酶降解，半衰期延长2~4倍[52]。MORI等[53]和HERSHKOVITZ等[54]的临床试验表明，与每日1次给予生长激素相比，每周给予Somatrogon1次治疗儿童GHD具有更好效果。3.2 单克隆抗体应用于儿童注射剂的单克隆抗体主要集中于呼吸系统疾病。西加韦单抗和替沙格韦单抗(cilgavimab/tixagevimab)是2种重组人免疫球蛋白G1k链单克隆抗体，其在抗体的Fc区进行氨基酸置换，通过影响抗体与免疫系统中其他分子的相互作用来延长抗体半衰期[55]。与传统抗体相比，半衰期可延长>3倍，成人和>12岁青少年(体质量≥40kg)单次给药后长达12个月有效。注射用奥马珠单抗也为重组人源化单克隆抗体，为抗免疫球蛋白E靶向生物制剂，适用于≥6岁患有中至重度持续性过敏性哮喘的儿童，每2~4周注射1次可维持疗效[56]。呼吸道合胞病毒(respiratory syncytial virus，RSV)是引起婴儿下呼吸道感染的主要原因[57]。单克隆抗体可作为疫苗替代品预防RSV感染。Nirsevimab是一种包含Fc突变片段且具有较长半衰期(平均59.3d)的RSV单克隆抗体[58]，临床数据表明，单剂量肌内注射Nirsevimab可实现婴儿至少5个月预防RSV感染[59]。2023年7月，首个用于预防婴幼儿RSV疾病的长效单克隆抗体Nirsevimab经FDA获批上市。目前Nirsevimab已在国内开展Ⅲ期临床试验。儿童用长效注射剂相关临床研究进展见表1。4展望与成人相比，儿童患者因年龄小、自我管理能力有限，对于一些慢性疾病(如GHD)往往需要长期甚至终身用药。频繁给药会给患儿带来不便与痛苦，且患儿依从性不足导致的治疗中断还会使病情恶化加重。长效注射剂则提供了更便捷的治疗方案，它通过延长药物作用时间，降低了治疗中断风险，提高了依从性[60]。本文全面综述了当前儿童用长效注射剂基础研究方面的进展情况，同时对其临床研究进展进行了系统总结。目前已上市的儿童用长效注射剂有生长激素、Cilgavimab/Tixagevimab、曲普瑞林微球制剂和卡博特韦/利匹韦林注射液Cabenuva等。此外，一部分长效药物已经进入Ⅲ期临床试验。很多学者在儿童疾病(如癌症、梗阻性肾病和炎症性疾病)方面进行了长效制剂的基础研究，以期推动长效注射剂的临床转化。儿童用长效注射剂在提升治疗依从性的同时，也面临一系列挑战和问题。就常见的儿童用长效制剂辅料而言，以PEG为例，其代谢产物会引发诸多不良状况，如导致酸中毒和高钙血症。融合蛋白可能出现新的抑制性抗体，这无疑给治疗带来了潜在风险。而在微球长效制剂中，形成微球的聚合物多孔表面使封装药物容易扩散而导致药物突释问题。另外，水凝胶长效制剂存在生物相容性差的问题，纳米晶长效制剂在给药后的体内过程和生物药剂学方面研究尚不充分。儿童用长效注射剂在提高依从性的同时，因可能导致非生理特性反应在体内产生相关不良反应，因而疗效、安全性方面存在极大挑战。而且其在制造及商业化方面也存在诸多问题。面对这些挑战，未来的发展方向应聚焦于精密设计药物结构及服用剂量，提供个性化基质与药物处方，从而研发出不影响药物疗效及稳定性、满足不同儿童用药需求的长效注射剂。在医学日益发达的背景下，基于儿童这一特殊人群的长效注射剂的发展具有广阔前景。PEG修饰、TransCon技术、非共价结合白蛋白、单克隆抗体、微球机制可应用于长效蛋白类药物。而包合物、纳米晶剂型可应用于长效化学药物。水凝胶、化学修饰机制在长效化药、蛋白类药物方面均有所应用。未来，长效注射剂有望在儿童癌症等重大疾病、哮喘等慢性呼吸系统疾病、生长发育迟缓等内分泌系统疾病以及疫苗研发等方面成为热点。参考文献详见《医药导报》 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