Research Progress of Osimertinib Supported by Nanodrug Delivery System Against Non-small Cell Lung Cancer
-
摘要:
奥希替尼是不可逆的第三代表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)，用于治疗经典EGFR突变和T790M耐药突变的非小细胞肺癌(NSCLC)。然而，与其他EGFR-TKIs一样，奥希替尼不可避免地存在获得性耐药、水溶性差、肿瘤累积率低等问题，限制了其治疗效果。纳米递药系统可增加药物的溶解度和稳定性，延长药物血液循环时间，提高细胞摄取率，增加在肿瘤组织中的聚集改善药物耐药问题，已成为解决传统靶向药物弊端的有效手段。本文综述了第三代EGFR-TKI奥希替尼的作用机制，重点阐述了奥希替尼纳米递药系统抗NSCLC的研究进展，并对该领域面临的挑战和未来发展方向进行了展望。
Abstract:Osimertinib is an irreversible third representative epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for the treatment of non-small cell lung cancer (NSCLC) with T790M resistance and classical EGFR mutations. However, the therapeutic effectiveness of osimertinib is limited by acquired drug-resistance, poor water solubility and low tumor accumulation rates. Nanodrug delivery systems can increase the solubility and stability of drugs, prolong the blood circulation time of drugs, improve the uptake rate of cells, promote drug accumulation in tumor tissues, and improve drug resistance. Thus, they are effective in overcoming the limitations of traditional targeted drugs. In this study, we reviewed the mechanism of action of the third-generation EGFR-TKI osimertinib, focused on research advances in osimertinib nanodrug delivery systems against NSCLC, and explored the challenges and future development direction in this field.
-
Key words:
- NSCLC /
- Osimertinib /
- Nanodrug delivery system
-
0 引言
中国胃癌患者平均死亡率高达20/10万，占恶性肿瘤的第一位[1]。究其原因可能与原发肿瘤致病基因突变、药物的敏感度反应、耐药机制多样性等异质性相关[2]，为此，探求早期预测生物学进展标志物成为研究热点。本研究应用ELISA法、多重RNA/DNA原位分析等方法，对ⅢB期胃癌术后患者辅助化疗后随访期内进行动态检测外周血癌胚抗原(carcino-embryonic antigen, CEA)、p21活化激酶5(p21-activated kinase 5, PAK5)、循环肿瘤细胞(circulating tumor cells, CTC)以及同时期CT检查，以期达到早期生物学预测复发转移的目的。
1 资料与方法
1.1 临床资料
收集2015年1月—2017年12月河北医科大学第四医院肿瘤内科胃癌根治术后完全缓解的患者150例。入组条件：术前晨空腹肘部外周静脉血CEA值超过正常值的5倍、术后病理诊断为胃腺癌ⅢB期(T4bN1-2M0、T4aN2M0、T3N3M0)(按照AJCC第七版)。治疗方案以奥沙利铂或紫杉醇为主的方案辅助化疗6周期，其中多西他赛为主方案72例，奥沙利铂为主方案78例。后续定期随访，每3月进行CEA检测和影像学评估。
分组标准：随访期内血浆CEA检测正常患者设为对照组，共50例。随访期内第一次CEA升高超过正常值5倍患者为实验组，共100例，同时按CEA水平增高不同情况，再分为两组：CEA进行性增高组(实验A组)和无规律增高组(实验B组)。
入组患者基线情况：入组时患者整体分期、化疗周期数、血浆癌胚抗原CEA、PAK5、CTC和影像学检查肿瘤病情评估差异均无统计学意义(P > 0.05)。所有患者按照住院或门诊评估的方式进行随访，随访截至2017年12月31日。
1.2 检测方法和频次
应用ELISA、多重RNA/DNA原位分析等方法，分别采集两组患者不同时刻的晨空腹肘部外周静脉血，检测血浆中癌胚抗原CEA、PAK5和CTC的水平。CEA由我院生化室完成检测。PAK5和CTC均由广州益善公司协助完成检测。
动态检测时间点的选择：T0：术前癌胚抗原超过正常值5倍; T1：术后辅助化疗6周期后; T2：CEA首次超过正常值5倍，本研究将其确定为生物学进展时间; T3：首次CT证实进展和(或)无影像学进展的患者随访截止时间。实验组动态检测三次(T1、T2、T3)，对照组动态检测两次(T1、T3)。
1.3 各指标阳性判定标准
癌胚抗原CEA阳性标准：CEA的正常值为 < 5 ng/ml。超过正常值的5倍为生物学进展阳性。CTC阳性标准：CTC检测分为上皮型、混合型、间质型，其中上皮型认定为良性，混合型认定为生物学进展，间质型认定为恶性复发转移，即为影像学进展，见图 1。PAK5检测标准：根据表达强度分为无表达、低表达、中表达、高表达。本研究判定标准：无表达和低表达为阴性，中表达和高表达为阳性，其中中表达/总细胞数的比率判定为生物学进展; 高表达/总细胞数的比率判定为影像进展，见图 2。
![]()
图 1 循环血肿瘤细胞CTC分型表达Figure 1 CTC typing of circulating tumor cells in bloodA: Epithelial type; B: Mixed type; C: Interstitial type.![]()
图 2 多重RNA原位分析PAK5表达情况Figure 2 In situ analysis of PAK5 expression by multiple RNAA: No expression; B: Low expression; C: Medium expression; D: High expression.2 结果
2.1 CEA与胃癌术后疾病进展关系
截至随访时间，对照组50例患者中均未见CEA增高，影像学未见明确病灶。实验两组中，按照生物学进展时间(T2)：实验A组为3~24月，中位时间13月。实验B组为4~32月，中位时间22月。按照影像进展时间(T3)：实验A组39例(78%)进展，出现时间为5~8月，中位时间为6.2月。实验B组12例(24%)进展，出现时间为4~15月，中位时间为10.6月。实验A组较B组更能提示复发转移。
2.2 CTC变化情况与胃癌术后疾病进展关系
T2时，实验A组混合型和间质型之和/总单细胞数比值大于30%，提示生物学进展; 间质型细胞数≥1在两实验组之间有差异，但无统计学意义。T3时，实验A组混合型和间质型之和/总单细胞数比值大于50%，提示影像学进展。间质型细胞数≥1在两实验组之间有差异，但病例数尚少，未行统计学分析，见表 1。
表 1 实验组CTC变化与ⅢB期胃癌术后患者肿瘤进展的关系Table 1 Relation between CTC change and tumor progression in patients with stage ⅢB gastric cancer after operation
2.3 PAK5变化与胃癌术后疾病进展关系
T2时，无表达、低表达、中表达数据没有偏移，两组间高表达数据有偏移; T3无表达、低表达数据没有偏移，两组间中、高表达数据有偏移。因为病例数尚少，未行统计学分析，见表 2。
表 2 PAK5表达与ⅢB期胃癌术后患者复发进展的关系Table 2 Relation between PAK5 expression and tumor progression in patients with stage ⅢB gastric cancer after operation
对明确影像学进展的51例患者的CTC细胞进行PAK5检测，中表达数值为13.6%~83%，高表达数值为37.8%~100%。
2.4 实验组CEA、PAK5、CTC三者阳性表达一致性
由于实验B组仅有12例(24%)患者影像学提示进展，病例数尚少，未行统计学分析。对实验A组39例影像学提示进展患者进行比较，T2时，CTC和PAK5、CEA判定的一致性为82%。T3时，和PAK5、CEA判定的一致性为94%。
3 讨论
中国ⅢB期胃癌术后5年生存率仅为15%~35%，究其原因在于部分患者术后即发生早期转移。临床上常常将癌胚抗原(CEA)作为ⅢB期胃癌术后随访复发转移的生物标志物[3]。本研究CEA进行性增高组(实验A组)有78%的患者肿瘤影像证实进展，有利于早期诊断复发转移。而CEA无规律增高组(实验B组)仅有24%提示肿瘤影像学进展，单指标检测存在假阳性，与文献报道CEA具有非特异性、易受炎性反应性疾病的干扰相一致。因此，提高预测指标的准确性成为临床研究的趋势，才能更好地避免给患者带来精神压力和过度治疗的可能性。
有研究报道CTC的间质型细胞具有恶性行为[4-6]，但对于混合型的恶性度报道不一，实体瘤的异质性导致的胃癌CTC的阳性标准不同于乳腺癌，尚无明确共识。本研究数据表明间质型细胞数大于1可早期预测影像学进展。但对于混合型的恶性度报道不一，本研究考虑混合型细胞具有恶性变的趋势，疾病进展演变成间质型，其演变过程是从肿瘤生物学进展发展到影像学进展的过程，可以很好地预测影像学进展。本研究应用统计学分析(混合型+间质型)/总单细胞数比值大于30%可早期预测生物学进展可能; (混合型+间质型)/总单细胞数比值大于50%可早期预测影像学进展可能。由于混合型细胞中有良性细胞成分和恶性成分，因本研究例数尚少，目前尚无更好的方法区分生物学进展，待扩大样本数后进一步进行验证。
为了更好的推算混合型向间质型细胞的演化时间，本研究增加检测了一种上游癌基因P21活化激酶亚型PAK5，有学者对恶性肿瘤组织标本检测数据表明PAK5过度表达或突变激活，参与了部分恶性实体瘤发生、发展[7-14]，但在胃癌中的研究较少[15-16]。本研究数据表明PAK5参与了胃癌细胞生长增殖的调节。PAK5的无/中表达表明肿瘤细胞进入复制分裂期的增殖数目较少、恶性度低; PAK5的中/高表达表明肿瘤细胞进入增殖期数目多、恶性度高。本研究明确影像学进展的51例患者生物学进展时刻时PAK5的中表达数值为13.6%~83%，高表达数值为37.8%~100%。结果显示PAK5的中/高表达可预测生物学进展，实验数据范围较广，我们考虑PAK5检测的敏感度和特异性可能会导致假阳性/假阴性。但因为例数较少，未行统计学分析。
本研究数据单因素检测存在误差，对癌培抗原进行性增高组影像学进展确定进展的39例患者进行CEA、PAK5、CTC三者联合检测的一致性上，预测生物学进展的一致率为82%;预测肿瘤影像学进展的一致率为94%，联合检测可提高预测率，降低检测误差。
因此，联合动态检测CEA、PAK5、CTC预测ⅢB期胃癌术后生物学进展，更早于影像进展诊断，可降低单一指标的假阳/阴性率，提高检出阳性率，防止漏诊、误诊的发生。
Competing interests: The authors declare that they have no competing interests.利益冲突声明：所有作者均声明不存在利益冲突。作者贡献：刘汝贵、赵瑞瑞：总结和归纳文献、文章撰写刘春朝、武晓：文章选题、指导、审校 -
[1] Bade BC, Dela Cruz CS. Lung Cancer 2020 Epidemiology, Etiology, and Prevention[J]. Clin Chest Med, 2020, 41(1): 1-24. doi: 10.1016/j.ccm.2019.10.001
[2] Howlader N, Forjaz G, Mooradian MJ, et al. The Effect of Advances in Lung-Cancer Treatment on Population Mortality[J]. N Engl J Med, 2020, 383(7): 640-649. doi: 10.1056/NEJMoa1916623
[3] Gelatti ACZ, Drilon A, Santini FC. Optimizing the sequencing of tyrosine kinase inhibitors (TKIs) in epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC)[J]. Lung Cancer, 2019, 137: 113-122. doi: 10.1016/j.lungcan.2019.09.017
[4] Hayashi H, Nadal E, Gray JE, et al. Overall Treatment Strategy for Patients With Metastatic NSCLC With Activating EGFR Mutations[J]. Clin Lung Cancer, 2022, 23(1): E69-E82. doi: 10.1016/j.cllc.2021.10.009
[5] Leonetti A, Sharma S, Minari R, et al. Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer[J]. Br J Cancer, 2019, 121(9): 725-737. doi: 10.1038/s41416-019-0573-8
[6] Yang J, Li YB, Sun JM, et al. An Osimertinib-Perfluorocarbon Nanoemulsion with Excellent Targeted Therapeutic Efficacy in Non-small Cell Lung Cancer: Achieving Intratracheal and Intravenous Administration[J]. ACS Nano, 2022, 16(8): 12590-12605. doi: 10.1021/acsnano.2c04159
[7] Khan KU, Minhas MU, Badshah SF, et al. Overview of nanoparticulate strategies for solubility enhancement of poorly soluble drugs[J]. Life Sci, 2022, 291: 120301. doi: 10.1016/j.lfs.2022.120301
[8] Peng SJ, Xiao FF, Chen MW, et al. Tumor-Microenvironment-Responsive Nanomedicine for Enhanced Cancer Immunotherapy[J]. Adv Sci, 2022, 9(1): 2103836. doi: 10.1002/advs.202103836
[9] Carcereny E, Moran T, Capdevila L, et al. The epidermal growth factor receptor (EGRF) in lung cancer[J]. Transl Respir Med, 2015, 3: 1. doi: 10.1186/s40247-015-0013-z
[10] Hassanein SS, Ibrahim SA, Abdel-Mawgood AL. Cell Behavior of Non-Small Cell Lung Cancer Is at EGFR and MicroRNAs Hands[J]. Int J Mol Sci, 2021, 22(22): 12496. doi: 10.3390/ijms222212496
[11] Da Cunha Santos G, Shepherd FA, Tsao MS. EGFR mutations and lung cancer[J]. Annu Rev Pathol, 2011, 6: 49-69. doi: 10.1146/annurev-pathol-011110-130206
[12] Uribe ML, Marrocco I, Yarden Y. EGFR in Cancer: Signaling Mechanisms, Drugs, and Acquired Resistance[J]. Cancers, 2021, 13(11): 2748. doi: 10.3390/cancers13112748
[13] Wu SG, Chang YL, Hsu YC, et al. Good Response to Gefitinib in Lung Adenocarcinoma of Complex Epidermal Growth Factor Receptor (EGFR) Mutations with the Classical Mutation Pattern[J]. Oncologist, 2008, 13(12): 1276-1284. doi: 10.1634/theoncologist.2008-0093
[14] Harrison PT, Vyse S, Huang PH. Rare epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer[J]. Semin Cancer Biol, 2020, 61: 167-179. doi: 10.1016/j.semcancer.2019.09.015
[15] Castellanos E, Feld E, Horn L. Driven by Mutations: The Predictive Value of Mutation Subtype in EGFR-Mutated Non-Small Cell Lung Cancer[J]. J Thorac Oncol, 2017, 12(4): 612-623. doi: 10.1016/j.jtho.2016.12.014
[16] Mithoowani H, Febbraro M. Non-Small-Cell Lung Cancer in 2022: A Review for General Practitioners in Oncology[J]. Curr Oncol, 2022, 29(3): 1828-1839. doi: 10.3390/curroncol29030150
[17] Ramalingam SS, Yang JCH, Lee CK, et al. Osimertinib As First-Line Treatment of EGFR Mutation-Positive Advanced Non-Small-Cell Lung Cancer[J]. J Clin Oncol, 2018, 36(9): 841-849. doi: 10.1200/JCO.2017.74.7576
[18] Lu S, Dong X R, Jian H, et al. AENEAS: A Randomized Phase Ⅲ Trial of Aumolertinib Versus Gefitinib as First-Line Therapy for Locally Advanced or Metastatic Non-Small-Cell Lung Cancer With EGFR Exon 19 Deletion or L858R Mutations[J]. J Clin Oncol, 2022, 40(27): 3162-3171. doi: 10.1200/JCO.21.02641
[19] Piper-Vallillo AJ, Sequist LV, Piotrowska Z. Emerging Treatment Paradigms for EGFR-Mutant Lung Cancers Progressing on Osimertinib: A Review[J]. J Clin Oncol, 2020, 38(25): 2926-2936. doi: 10.1200/JCO.19.03123
[20] Zeng Y, Yu DL, Tian WT, et al. Resistance mechanisms to osimertinib and emerging therapeutic strategies in nonsmall cell lung cancer[J]. Curr Opin Oncol, 2022, 34(1): 54-65. doi: 10.1097/CCO.0000000000000805
[21] He J, Huang Z, Han L, et al. Mechanisms and management of 3rd-generation EGFR-TKI resistance in advanced non-small cell lung cancer (Review)[J]. Int J Oncol, 2021, 59(5): 90. doi: 10.3892/ijo.2021.5270
[22] Liu Q, Yu S, Zhao W, et al. EGFR-TKIs resistance via EGFR-independent signaling pathways[J]. Mol Cancer, 2018, 17(1): 53. doi: 10.1186/s12943-018-0793-1
[23] Etheridge ML, Campbell SA, Erdman AG, et al. The big picture on nanomedicine: the state of investigational and approved nanomedicine products[J]. Nanomedicine, 2013, 9(1): 1-14. doi: 10.1016/j.nano.2012.05.013
[24] Ramasamy T, Ruttala HB, Gupta B, et al. Smart chemistry-based nanosized drug delivery systems for systemic applications: A comprehensive review[J]. J Control Release, 2017, 258. 226-253. doi: 10.1016/j.jconrel.2017.04.043
[25] Xu XY, Ho W, Zhang XQ, et al. Cancer nanomedicine: from targeted delivery to combination therapy[J]. Trends Mol Med, 2015, 21(4): 223-232. doi: 10.1016/j.molmed.2015.01.001
[26] Jahangirian H, Lemraski EG, Webster TJ, et al. A review of drug delivery systems based on nanotechnology and green chemistry: green nanomedicine[J]. Int J Nanomedicine, 2017, 12. 2957-2978. doi: 10.2147/IJN.S127683
[27] Caster JM, Patel AN, Zhang T, et al. Investigational nanomedicines in 2016: a review of nanotherapeutics currently undergoing clinical trials[J]. Wiley Interdiscip Rev Nanomed Nanobiotechnol, 2017, 9(1).
[28] Soejima K, Yasuda H, Hirano T. Osimertinib for EGFR T790M mutation-positive non-small cell lung cancer[J]. Expert Rev Clin Pharmacol, 2017, 10(1): 31-38. doi: 10.1080/17512433.2017.1265446
[29] Goss G, Tsai CM, Shepherd FA, et al. Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study[J]. Lancet Oncol, 2016, 17(12): 1643-1652. doi: 10.1016/S1470-2045(16)30508-3
[30] Hu XC, Chen SM, Yin H, et al. Chitooligosaccharides-modified PLGA nanoparticles enhance the antitumor efficacy of AZD9291 (Osimertinib) by promoting apoptosis[J]. Int J Biol Macromol, 2020, 162: 262-272. doi: 10.1016/j.ijbiomac.2020.06.154
[31] Guardiola S, Sanchez-Navarro M, Rosell R, et al. Anti-EGF nanobodies enhance the antitumoral effect of osimertinib and overcome resistance in non-small cell lung cancer (NSCLC) cellular models[J]. Med Oncol, 2022, 39(12): 195. doi: 10.1007/s12032-022-01800-1
[32] Izci M, Maksoudian C, Manshian BB, et al. The Use of Alternative Strategies for Enhanced Nanoparticle Delivery to Solid Tumors[J]. Chem Rev, 2021, 121(3): 1746-1803. doi: 10.1021/acs.chemrev.0c00779
[33] Kang H, Rho S, Stiles WR, et al. Size-Dependent EPR Effect of Polymeric Nanoparticles on Tumor Targeting[J]. Adv Healthc Mater, 2020, 9(1): 1901223. doi: 10.1002/adhm.201901223
[34] Ulldemolins A, Seras-Franzoso J, Andrade F, et al. Perspectives of nano-carrier drug delivery systems to overcome cancer drug resistance in the clinics[J]. Cancer Drug Resist, 2021, 4(1): 44-68.
[35] Kaushik N, Borkar SB, Nandanwar SK, et al. Nanocarrier cancer therapeutics with functional stimuli-responsive mechanisms[J]. J Nanobiotechnol, 2022, 20(1): 152. doi: 10.1186/s12951-022-01364-2
[36] Kravanja G, Primozic M, Knez Z, et al. Chitosan-Based (Nano)Materials for Novel Biomedical Applications[J]. Molecules, 2019, 24(10): 960.
[37] Cao Y, Tan YF, Wong YS, et al. Recent Advances in Chitosan-Based Carriers for Gene Delivery[J]. Mar Drugs, 2019, 17(6): 381. doi: 10.3390/md17060381
[38] Kumar SK, Choppala AD. Development and Optimization of Osimertinib-loaded Biodegradable Polymeric Nanoparticles Enhance In-vitro Cytotoxicity in Mutant EGFR NSCLC Cell Models and In-vivo Tumor Reduction in H1975 Xenograft Mice Models[J]. Aaps Pharmscitech, 2022, 23(5): 159. doi: 10.1208/s12249-022-02314-9
[39] Gu JJ, Yao WL, Shi PY, et al. MEK or ERK inhibition effectively abrogates emergence of acquired osimertinib resistance in the treatment of epidermal growth factor receptor-mutant lung cancers[J]. Cancer, 2020, 126(16): 3788-3799. doi: 10.1002/cncr.32996
[40] Li YT, Zang HJ, Qian GQ, et al. ERK inhibition effectively overcomes acquired resistance of epidermal growth factor receptor-mutant non-small-cell lung cancer cells to osimertinib[J]. Cancer, 2020, 126(6): 1339-1350. doi: 10.1002/cncr.32655
[41] Chen W, Yu DL, Sun SY, et al. Nanoparticles for co-delivery of osimertinib and selumetinib to overcome osimertinib-acquired resistance in non-small cell lung cancer[J]. Acta Biomater, 2021, 129: 258-268. doi: 10.1016/j.actbio.2021.05.018
[42] Zhang QN, Yie GQ, Li Y, et al. Studies on the cyclosporin A loaded stearic acid nanoparticles[J]. Int J Pharm, 2000, 200(2): 153-159. doi: 10.1016/S0378-5173(00)00361-6
[43] Trombino S, Russo R, Mellace S, et al. Solid lipid nanoparticles made of trehalose monooleate for cyclosporin-A topic release[J]. J Drug Deliv Sci Technol, 2019, 49: 563-569. doi: 10.1016/j.jddst.2018.12.026
[44] Chen SM, Ji XG, Zhao MY, et al. Construction of chitooligosaccharide-based nanoparticles of pH/redox cascade responsive for co-loading cyclosporin A and AZD9291[J]. Carbohydr Polym, 2022, 291: 1119619.
[45] Chen Q, Huang GJ, Wu WT, et al. A Hybrid Eukaryotic-Prokaryotic Nanoplatform with Photothermal Modality for Enhanced Antitumor Vaccination[J]. Adv Mater, 2020, 32(16): 1908185. doi: 10.1002/adma.201908185
[46] Xu B, Zeng FJ, Deng JL, et al. A homologous and molecular dual-targeted biomimetic nanocarrier for EGFR-related non-small cell lung cancer therapy[J]. Bioact Mater, 2023, 27: 337-347.
[47] Ren MX, Li YZ, Zhang H, et al. An oligopeptide/aptamer-conjugated dendrimer-based nanocarrier for dual-targeting delivery to bone[J]. J Mat Chem B, 2021, 9(12): 2831-2844. doi: 10.1039/D0TB02926B
[48] Shen SH, Wu YS, Liu YC, et al. High drug-loading nanomedicines: progress, current status, and prospects[J]. Int J Nanomed, 2017, 12. 4085-4109. doi: 10.2147/IJN.S132780
[49] Vega-Villa KR, Takemoto JK, Yanez JA, et al. Clinical toxicities of nanocarrier systems[J]. Adv Drug Deliv Rev, 2008, 60(8): 929-938. doi: 10.1016/j.addr.2007.11.007
[50] Pingale P, Kendre P, Pardeshi K, et al. An emerging era in manufacturing of drug delivery systems: Nanofabrication techniques[J]. Heliyon, 2023, 9(3): e14247. doi: 10.1016/j.heliyon.2023.e14247
[51] Huang L, Zhao SJ, Fang F, et al. Advances and perspectives in carrier-free nanodrugs for cancer chemo-monotherapy and combination therapy[J]. Biomaterials, 2021, 268. 120557. doi: 10.1016/j.biomaterials.2020.120557
[52] Yang MY, Zhao RR, Fang YF, et al. Carrier-free nanodrug: A novel strategy of cancer diagnosis and synergistic therapy[J]. Int J Pharm, 2019, 570: 118663. doi: 10.1016/j.ijpharm.2019.118663
[53] Liu LH, Zhang XZ. Carrier-free nanomedicines for cancer treatment[J]. Prog Mater Sci, 2022, 125: 100919. doi: 10.1016/j.pmatsci.2021.100919
[54] Fu SW, Li GT, Zang WL, et al. Pure drug nano-assemblies: A facile carrier-free nanoplatform for efficient cancer therapy[J]. Acta Pharm Sin B, 2022, 12(1): 92-106. doi: 10.1016/j.apsb.2021.08.012
[55] Mei H, Cai SS, Huang DN, et al. Carrier-free nanodrugs with efficient drug delivery and release for cancer therapy: From intrinsic physicochemical properties to external modification[J]. Bioact Mater, 2022, 8: 220-240.
[56] Han HS, Choi KY. Advances in Nanomaterial-Mediated Photothermal Cancer Therapies: Toward Clinical Applications[J]. Biomedicines, 2021, 9(3): 305. doi: 10.3390/biomedicines9030305
[57] Correia JH, Rodrigues JA, Pimenta S, et al. Photodynamic Therapy Review: Principles, Photosensitizers, Applications, and Future Directions[J]. Pharmaceutics, 2021, 13(9): 1332. doi: 10.3390/pharmaceutics13091332
[58] Yang L, Huang B, Hu SQ, et al. Indocyanine green assembled free oxygen-nanobubbles towards enhanced near-infrared induced photodynamic therapy[J]. Nano Res, 2022, 15(5): 4285-4293. doi: 10.1007/s12274-022-4085-0
[59] Hu XY, Li JW, Chen YL, et al. A Self-Assembly ICG Nanoparticle Potentiating Targeted Photothermal and Photodynamic Therapy in NSCLC[J]. ACS Biomater Sci Eng, 2022, 8(10): 4535-4546. doi: 10.1021/acsbiomaterials.2c00620
-
期刊类型引用(5)
1. 王放明，乔新伟，陈玖玲，刘红菊，赵峰. 非小细胞肺癌组织PAK4、PAK5蛋白表达与上皮-间质转化、临床病理特征和预后的关系分析. 现代生物医学进展. 2024(02): 253-257+293 . 
百度学术
2. 卢云锋，王志军. 术前术后癌胚抗原差值对胃癌患者腹腔镜辅助远端胃癌根治术后复发的影响. 河南医学研究. 2024(16): 2958-2961 . 百度学术
3. 李媛媛，甘苓伶，杨志昊. 胃癌根治术患者外周血CEA、AFP、PG Ⅰ的表达及与术后复发率的关系. 川北医学院学报. 2023(02): 233-236 . 百度学术
4. 霍晶，高琪磊，沈琪琪，蒋慈原，范晓芳. 超声造影定量参数联合癌胚抗原、中性粒细胞/淋巴细胞比值对乳腺癌改良根治术后复发转移的预测价值. 现代生物医学进展. 2023(22): 4289-4293+4314 . 百度学术
5. 许诗燕. 胃癌患者血清指标水平与病理特征的相关性. 实用中西医结合临床. 2022(23): 82-84+128 . 百度学术
其他类型引用(0)
下载:
计量
- 文章访问数: 1210
- HTML全文浏览量: 2238
- PDF下载量: 1237
- 被引次数: 5
