药学学报, 2021, 56(5): 1332-1342
引用本文:
蒋小宏, 邢续扬, 王孝春, 尹莉芳, 何伟*. 肺动脉高压的药物治疗及药物递送策略[J]. 药学学报, 2021, 56(5): 1332-1342.
JIANG Xiao-hong, XING Xu-yang, WANG Xiao-chun, YIN Li-fang, HE Wei*. Drugs and drug delivery strategies for treatment of pulmonary arterial hypertension[J]. Acta Pharmaceutica Sinica, 2021, 56(5): 1332-1342.

肺动脉高压的药物治疗及药物递送策略
蒋小宏, 邢续扬, 王孝春, 尹莉芳, 何伟*
中国药科大学药学院, 江苏 南京 211198
摘要:
肺动脉高压(pulmonary arterial hypertension,PAH)属于罕见性疾病,被称为“心血管疾病中的癌症”,其发病机制复杂。近年来,PAH发病机制的研究取得了一定的进展。针对病理机制与作用途径,目前临床治疗药物主要包括前列环素类似物和前列环素受体激动剂、内皮素受体拮抗剂、磷酸二酯酶-5抑制剂和可溶性鸟苷酸环化酶抑制剂等。为了改善这些药物的治疗作用,也开发了多种递药系统。本文介绍了PAH的发病机制,并重点介绍了PAH的治疗药物及药物递送策略等。
关键词:    药剂学      肺动脉高压      药物递送      药物治疗     
Drugs and drug delivery strategies for treatment of pulmonary arterial hypertension
JIANG Xiao-hong, XING Xu-yang, WANG Xiao-chun, YIN Li-fang, HE Wei*
School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China
Abstract:
Pulmonary arterial hypertension (PAH), also named as a cancer of cardiovascular disease, is a rare disease and has complicated pathogenesis. Recently, there are more understandings of PAH pathogeneses. According to the pathogenesis and active pathways, the clinically used drugs are classified into several groups incluidng prostacyclin analogues and prostacyclin receptor agonists, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, soluble guanylate cyclase inhibitors, etc. To elevate the efficacy of the drugs, numerous drug delivery systems are developed. This review mainly summarized the pathological mechanism of PAH, drugs and drug delivery approaches in the treatment of PAH.
Key words:    pharmaceutics    pulmonary arterial hypertension    drug delivery    therapy   
收稿日期: 2020-12-09
DOI: 10.16438/j.0513-4870.2020-1896
基金项目: 国家自然科学基金资助项目(81872823,82073782);上海市科学技术委员会资助项目(19430741500).
通讯作者: 何伟,Tel:15295798691,E-mail:weihe@cpu.edu.cn
Email: weihe@cpu.edu.cn
相关功能
PDF(1198KB) Free
打印本文
0
作者相关文章
蒋小宏  在本刊中的所有文章
邢续扬  在本刊中的所有文章
王孝春  在本刊中的所有文章
尹莉芳  在本刊中的所有文章
何伟*  在本刊中的所有文章

参考文献:
[1] Avitabile CM, Vorhies EE, Ivy DD. Drug treatment of pulmonary hypertension in children[J]. Paediatr Drugs, 2020, 22:123-147.
[2] Rabinovitch M, Guignabert C, Humbert M, et al. Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension[J]. Circ Res, 2014, 115:165-175.
[3] Ivy DD, Doran A, Claussen L, et al. Weaning and discontinuation of epoprostenol in children with idiopathic pulmonary arterial hypertension receiving concomitant bosentan[J]. Am J Cardiol, 2004, 93:943-946.
[4] Ruan KH. Advance in understanding the biosynthesis of prostacyclin and thromboxane A2 in the endoplasmic reticulum membrane via the cyclooxygenase pathway[J]. Mini Rev Med Chem, 2004, 4:639-647.
[5] Gupta V, Davis M, Hope-Weeks LJ,et al. PLGA microparticles encapsulating prostaglandin E 1-hydroxypropyl-beta-cyclodextrin (PGE1-HPbetaCD) complex for the treatment of pulmonary arterial hypertension (PAH)[J]. Pharm Res, 2011, 28:1733-1749.
[6] Gupta V, Ahsan F. Influence of PEI as a core modifying agent on PLGA microspheres of PGE(1), a pulmonary selective vasodilator[J]. Int J Pharm, 2011, 413:51-62.
[7] Gupta V, Gupta N, Shaik IH, et al. Inhaled PLGA particles of prostaglandin E(1) ameliorate symptoms and progression of pulmonary hypertension at a reduced dosing frequency[J]. Mol Pharm, 2013, 10:1655-1667.
[8] Jain PP, Leber R, Nagaraj C, et al. Liposomal nanoparticles encapsulating iloprost exhibit enhanced vasodilation in pulmonary arteries[J]. Int J Nanomedicine, 2014, 9:3249-3261.
[9] Zare P, Heller D. Treprostinil[M]//StatPearls. Treasure Island (FL):StatPearls Publishing, 2020.
[10] Skoro-Sajer N, Lang I. Extended-release oral treprostinil for the treatment of pulmonary arterial hypertension[J]. Expert Rev Cardiovasc Ther, 2014, 12:1391-1399.
[11] Leifer FG, Konicek DM, Chen KJ, et al. Inhaled treprostinil-prodrug lipid nanoparticle formulations provide long-acting pulmonary vasodilation[J]. Drug Res, 2018, 68:605-614.
[12] Akagi S, Nakamura K, Matsubara H, et al. Intratracheal administration of prostacyclin analogue-incorporated nanoparticles ameliorates the development of monocrotaline and sugen-hypoxia-induced pulmonary arterial hypertension[J]. J Cardiovasc Pharmacol, 2016, 67:290-298.
[13] Shen L, Patel JA, Norel X, et al. Pharmacology of the single isomer, esuberaprost (beraprost-314d) on pulmonary vascular tone, IP receptors and human smooth muscle proliferation in pulmonary hypertension[J]. Biochem Pharmacol, 2019, 166:242-252.
[14] Lee HJ, Kang JH, Lee HG, et al. Preparation and physicochemical characterization of spray-dried and jet-milled microparticles containing bosentan hydrate for dry powder inhalation aerosols[J]. Drug Des Devel Ther, 2016, 10:4017-4030.
[15] Hanna LA, Basalious EB, On EL. Respirable controlled release polymeric colloid (RCRPC) of bosentan for the management of pulmonary hypertension:in vitro aerosolization, histological examination and in vivo pulmonary absorption[J]. Drug Deliv, 2016, 24:188-198.
[16] Gimenez VM, Sperandeo N, Faudone S, et al. Preparation and characterization of bosentan monohydrate/epsilon-polycaprolactone nanoparticles obtained by electrospraying[J]. Biotechnol Prog, 2019, 35:e2748.
[17] Deshmane S, Deshmane S, Shelke S, et al. Enhancement of solubility and bioavailability of ambrisentan by solid dispersion using Daucus carota as a drug carrier:formulation, characterization, in vitro, and in vivo study[J]. Drug Dev Ind Pharm, 2018, 44:1001-1011.
[18] Zeng FB, Lu B, Yang H, et al. Studies on gelatin microsphere loaded ligustrazine hydrochloride for lung targeting[J]. Acta Pharm Sin (药学学报), 1996, 31:132-137.
[19] Pullamsetti S, Krick S, Yilmaz H, et al. Inhaled tolafentrine reverses pulmonary vascular remodeling via inhibition of smooth muscle cell migration[J]. Respir Res, 2005, 6:128.
[20] Bhogal S, Khraisha O, Al Madani M, et al. Sildenafil for pulmonary arterial hypertension[J]. Am J Ther, 2019, 26:e520-e526.
[21] Makled S, Nafee N, Boraie N. Nebulized solid lipid nanoparticles for the potential treatment of pulmonary hypertension via targeted delivery of phosphodiesterase-5-inhibitor[J]. Int J Pharm, 2017, 517:312-321.
[22] Nafee N, Makled S, Boraie N. Nanostructured lipid carriers versus solid lipid nanoparticles for the potential treatment of pulmonary hypertension via nebulization[J]. Eur J Pharm Sci, 2018, 125:151-162.
[23] Rashid J, Patel B, Nozik-Grayck E, et al. Inhaled sildenafil as an alternative to oral sildenafil in the treatment of pulmonary arterial hypertension (PAH)[J]. J Control Release, 2017, 250:96-106.
[24] Beck-Broichsitter M, Bohr A, Aragao-Santiago L, et al. Formulation and process considerations for the design of sildenafil-loaded polymeric microparticles by vibrational spray-drying[J]. Pharm Dev Technol, 2017, 22:691-698.
[25] Li B, He W, Ye L, et al. Targeted delivery of sildenafil for inhibiting pulmonary vascular remodeling[J]. Hypertension, 2019, 73:703-711.
[26] Bowles EA, Feys D, Ercal N, et al. Liposomal-delivery of phosphodiesterase 5 inhibitors augments UT-15C-stimulated ATP release from human erythrocytes[J]. Biochem Biophys Rep, 2017, 12:114-119.
[27] Lu M, Xing H, Yang T, et al. Dissolution enhancement of tadalafil by liquisolid technique[J]. Pharm Dev Technol, 2017, 22:77-89.
[28] Varshosaz J, Taymouri S, Hamishehkar H, et al. Development of dry powder inhaler containing tadalafil-loaded PLGA nanoparticles[J]. Res Pharm Sci, 2017, 12:222-232.
[29] Teymouri Rad R, Dadashzadeh S, Vatanara A, et al. Tadalafil nanocomposites as a dry powder formulation for inhalation, a new strategy for pulmonary arterial hypertension treatment[J]. Eur J Pharm Sci, 2019, 133:275-286.
[30] Elbardisy B, Galal S, Abdelmonsif DA, et al. Intranasal tadalafil nanoemulsions:formulation, characterization and pharmacodynamic evaluation[J]. Pharm Dev Technol, 2019, 24:1083-1094.
[31] Jacobs BR, Brilli RJ, Ballard ET, et al. Aerosolized soluble nitric oxide donor improves oxygenation and pulmonary hypertension in acute lung injury[J]. Am J Respir Crit Care Med, 1998, 158:1536-1542.
[32] Puikuan K, Chunyu Z, Jin F, et al. Inhalation of nebulized nitroglycerin, a nitric oxide donor, for the treatment of pulmonary hypertension induced by high pulmonary blood flow[J]. Heart Vessels, 2006, 21:169-179.
[33] Evgenov OV, Kohane DS, Bloch KD, et al. Inhaled agonists of soluble guanylate cyclase induce selective pulmonary vasodilation[J]. Am J Respir Crit Care Med, 2007, 176:1138-1145.
[34] Saigal A, Ng WK, Tan RB, et al. Development of controlled release inhalable polymeric microspheres for treatment of pulmonary hypertension[J]. Int J Pharm, 2013, 450:114-122.
[35] Woodmansey PA, O'Toole L, Channer KS, et al. Acute pulmonary vasodilatory properties of amlodipine in humans with pulmonary hypertension[J]. Heart, 1996, 75:171-173.
[36] Minami M, Arita T, Iwasaki H, et al. Comparative analysis of pulmonary hypertension in patients treated with imatinib, nilotinib and dasatinib[J]. Br J Haematol, 2017, 177:578-587.
[37] Patterson KC, Weissmann A, Ahmadi T, et al. Imatinib mesylate in the treatment of refractory idiopathic pulmonary arterial hypertension[J]. Ann Intern Med, 2006, 145:152-153.
[38] Kimura G, Kataoka M, Inami T, et al. Sorafenib as a potential strategy for refractory pulmonary arterial hypertension[J]. Pulm Pharmacol Ther, 2017, 44:46-49.
[39] Toba M, Alzoubi A, O'Neill K, et al. A novel vascular homing peptide strategy to selectively enhance pulmonary drug efficacy in pulmonary arterial hypertension[J]. Am J Pathol, 2014, 184:369-375.
[40] Akagi S, Nakamura K, Miura D, et al. Delivery of imatinib-incorporated nanoparticles into lungs suppresses the development of monocrotaline-induced pulmonary arterial hypertension[J]. Int Heart J, 2015, 56:354-359.
[41] McMurtry MS, Bonnet S, Wu X, et al. Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis[J]. Circ Res, 2004, 95:830-840.
[42] Hawwa N, Menon V. Ranolazine:clinical applications and therapeutic basis[J]. Am J Cardiovasc Drugs, 2013, 13:5-16.
[43] Sutendra G, Bonnet S, Rochefort G, et al. Fatty acid oxidation and malonyl-CoA decarboxylase in the vascular remodeling of pulmonary hypertension[J]. Sci Transl Med, 2010, 2:44ra58.
[44] Evgenov OV, Kohane DS, Bloch KD, et al. Inhaled agonists of soluble guanylate cyclase induce selective pulmonary vasodilation[J]. Am J Resp Crit Care, 2007, 176:1138-1145.
[45] Spiekerkoetter E, Sung YK, Sudheendra D, et al. Low-dose FK506(tacrolimus) in end-stage pulmonary arterial hypertension[J]. Am J Respir Crit Care Med, 2015, 192:254-257.
[46] Sommer N, Droege F, Gamen KE, et al. Treatment with low-dose tacrolimus inhibits bleeding complications in a patient with hereditary hemorrhagic telangiectasia and pulmonary arterial hypertension[J]. Pulm Circ, 2019, 9:2045894018805406.
[47] Akagi S, Nakamura K, Miura D, et al. Delivery of imatinib-incorporated nanoparticles into lungs suppresses the development of monocrotaline-induced pulmonary arterial hypertension[J]. Int Heart J, 2015, 56:354-359.
[48] Alapati D, Rong M, Chen S, et al. Inhibition of LRP5/6-mediated Wnt/beta-catenin signaling by Mesd attenuates hyperoxia-induced pulmonary hypertension in neonatal rats[J]. Pediatr Res, 2013, 73:719-725.
[49] Alapati D, Rong M, Chen S, et al. Inhibition of beta-catenin signaling improves alveolarization and reduces pulmonary hypertension in experimental bronchopulmonary dysplasia[J]. Am J Respir Cell Mol Biol, 2014, 51:104-113.
[50] Kimura S, Egashira K, Chen L, et al. Nanoparticle-mediated delivery of nuclear factor kappaB decoy into lungs ameliorates monocrotaline-induced pulmonary arterial hypertension[J]. Hypertension, 2009, 53:877-883.
[51] Wang Z, Cuddigan JL, Gupta SK, et al. Nanocomposite microparticles (nCmP) for the delivery of tacrolimus in the treatment of pulmonary arterial hypertension[J]. Int J Pharm, 2016, 512:305-313.
[52] Brousseau S, Wang Z, Gupta SK, et al. Development of aerosol phospholipid microparticles for the treatment of pulmonary hypertension[J]. AAPS PharmSciTech, 2017, 18:3247-3257.
[53] Sun XZ, Tian XY, Wang DW, et al. Effects of fasudil on hypoxic pulmonary hypertension and pulmonary vascular remodeling in rats[J]. Eur Rev Med Pharmacol Sci, 2014, 18:959-964.
[54] Chen XY, Dun JN, Miao QF, et al. Fasudil hydrochloride hydrate, a Rho-kinase inhibitor, suppresses 5-hydroxytryptamine-induced pulmonary artery smooth muscle cell proliferation via JNK and ERK1/2 pathway[J]. Pharmacology, 2009, 83:67-79.
[55] Gupta N, Patel B, Nahar K, et al. Cell permeable peptide conjugated nanoerythrosomes of fasudil prolong pulmonary arterial vasodilation in PAH rats[J]. Eur J Pharm Biopharm, 2014, 88:1046-1055.
[56] Qi L, Lv T, Cheng Y, et al. Fasudil dichloroacetate (FDCA), an orally available agent with potent therapeutic efficiency on monocrotaline-induced pulmonary arterial hypertension rats[J]. Bioorg Med Chem Lett, 2019, 29:1812-1818.
[57] Gupta N, Patel B, Ahsan F. Nano-engineered erythrocyte ghosts as inhalational carriers for delivery of fasudil:preparation and characterization[J]. Pharm Res, 2014, 31:1553-1565.
[58] Gupta N, Ibrahim HM, Ahsan F. Peptide-micelle hybrids containing fasudil for targeted delivery to the pulmonary arteries and arterioles to treat pulmonary arterial hypertension[J]. J Pharm Sci, 2014, 103:3743-3753.
[59] Gupta V, Gupta N, Shaik IH, et al. Liposomal fasudil, a rho-kinase inhibitor, for prolonged pulmonary preferential vasodilation in pulmonary arterial hypertension[J]. J Control Release, 2013, 167:189-199.
[60] Nahar K, Absar S, Patel B, et al. Starch-coated magnetic liposomes as an inhalable carrier for accumulation of fasudil in the pulmonary vasculature[J]. Int J Pharm, 2014, 464:185-195.
[61] Wang HM, Wang Y, Liu M, et al. Fluoxetine inhibits monocrotaline-induced pulmonary arterial remodeling involved in inhibition of RhoA-Rho kinase and Akt signalling pathways in rats[J]. Can J Physiol Pharmacol, 2012, 90:1506-1515.
[62] Zhai FG, Zhang XH, Wang HL. Fluoxetine protects against monocrotaline-induced pulmonary arterial hypertension:potential roles of induction of apoptosis and upregulation of Kv1.5 channels in rats[J]. Clin Exp Pharmacol Physiol, 2009, 36:850-856.
[63] Bhat L, Hawkinson J, Cantillon M, et al. RP5063, a novel, multimodal, serotonin receptor modulator, prevents monocrotaline-induced pulmonary arterial hypertension in rats[J]. Eur J Pharmacol, 2017, 810:92-99.
[64] Bhat L, Hawkinson J, Cantillon M, et al. RP5063, a novel, multimodal, serotonin receptor modulator, prevents Sugen 5416-hypoxia-induced pulmonary arterial hypertension in rats[J]. Eur J Pharmacol, 2017, 810:83-91.
[65] Chen L, Nakano K, Kimura S, et al. Nanoparticle-mediated delivery of pitavastatin into lungs ameliorates the development and induces regression of monocrotaline-induced pulmonary artery hypertension[J]. Hypertension, 2011, 57:343-350.
[66] Ichimura K, Matoba T, Koga JI, et al. Nanoparticle-mediated targeting of pitavastatin to small pulmonary arteries and leukocytes by intravenous administration attenuates the progression of monocrotaline-induced established pulmonary arterial hypertension in rats[J]. Int Heart J, 2018, 59:1432-1444.
[67] Lee Y, Pai SB, Bellamkonda RV, et al. Cerivastatin nanoliposome as a potential disease modifying approach for the treatment of pulmonary arterial hypertension[J]. J Pharmacol Exp Ther, 2018, 366:66-74.
[68] Liparulo A, Esposito R, Santonocito D, et al. Formulation and characterization of solid lipid nanoparticles loading RF22-c, a potent and selective 5-LO inhibitor, in a monocrotaline-induced model of pulmonary hypertension[J]. Front Pharmacol, 2020, 11:83.
[69] Crossno JT Jr, Garat CV, Reusch JE, et al. Rosiglitazone attenuates hypoxia-induced pulmonary arterial remodeling[J]. Am J Physiol Lung Cell Mol Physiol, 2007, 292:L885-L897.
[70] Liu Y, Tian XY, Mao G, et al. Peroxisome proliferator-activated receptor-gamma ameliorates pulmonary arterial hypertension by inhibiting 5-hydroxytryptamine 2B receptor[J]. Hypertension, 2012, 60:1471-1478.
[71] Rashid J, Alobaida A, Al-Hilal TA, et al. Repurposing rosiglitazone, a PPAR-gamma agonist and oral antidiabetic, as an inhaled formulation, for the treatment of PAH[J]. J Control Release, 2018, 280:113-123.
[72] Segura-Ibarra V, Amione-Guerra J, Cruz-Solbes AS, et al. Rapamycin nanoparticles localize in diseased lung vasculature and prevent pulmonary arterial hypertension[J]. Int J Pharm, 2017, 524:257-267.
[73] Gupta N, Al-Saikhan FI, Patel B, et al. Fasudil and SOD packaged in peptide-studded-liposomes:properties, pharmacokinetics and ex-vivo targeting to isolated perfused rat lungs[J]. Int J Pharm, 2015, 488:33-43.
[74] Gupta N, Rashid J, Nozik-Grayck E, et al. Cocktail of superoxide dismutase and fasudil encapsulated in targeted liposomes slows PAH progression at a reduced dosing frequency[J]. Mol Pharm, 2017, 14:830-841.
[75] Rashid J, Nahar K, Raut S, et al. Fasudil and DETA NONOate, loaded in a peptide-modified liposomal carrier, slow PAH progression upon pulmonary delivery[J]. Mol Pharm, 2018, 15:1755-1765.
[76] Rashid J, Nozik-Grayck E, McMurtry IF, et al. Inhaled combination of sildenafil and rosiglitazone improves pulmonary hemodynamics, cardiac function, and arterial remodeling[J]. Am J Physiol Lung Cell Mol Physiol, 2019, 316:L119-L130.
[77] Gill KK, Nazzal S, Kaddoumi A. Paclitaxel loaded PEG(5000)-DSPE micelles as pulmonary delivery platform:formulation characterization, tissue distribution, plasma pharmacokinetics, and toxicological evaluation[J]. Eur J Pharm Biopharm, 2011, 79:276-284.
[78] Yin Y, Wu X, Yang Z, et al. The potential efficacy of R8-modified paclitaxel-loaded liposomes on pulmonary arterial hypertension[J]. Pharm Res, 2013, 30:2050-2062.
[79] Patel B, Gupta V, Ahsan F. PEG-PLGA based large porous particles for pulmonary delivery of a highly soluble drug, low mole-cular weight heparin[J]. J Control Release, 2012, 162:310-320.
[80] Mali AJ, Bothiraja C, Purohit RN, et al. In vitro and in vivo performance of novel spray dried andrographolide loaded scleroglucan based formulation for dry powder inhaler[J]. Curr Drug Deliv, 2017, 14:968-980.
[81] Carregal-Romero S, Fadon L, Berra E, et al. MicroRNA nanotherapeutics for lung targeting. Insights into pulmonary hypertension[J]. Int J Mol Sci, 2020, 21:3253.
[82] Bivas-Benita M, Romeijn S, Junginger HE, et al. PLGA-PEI nanoparticles for gene delivery to pulmonary epithelium[J]. Eur J Pharm Biopharm, 2004, 58:1-6.
[83] Garbuzenko OB, Saad M, Betigeri S, et al. Intratracheal versus intravenous liposomal delivery of siRNA, antisense oligonucleotides and anticancer drug[J]. Pharm Res, 2009, 26:382-394.
[84] McLendon JM, Joshi SR, Sparks J, et al. Lipid nanoparticle delivery of a microRNA-145 inhibitor improves experimental pulmonary hypertension[J]. J Control Release, 2015, 210:67-75.
[85] Takahashi M, Nakamura T, Toba T, et al. Transplantation of endothelial progenitor cells into the lung to alleviate pulmonary hypertension in dogs[J]. Tissue Eng, 2004, 10:771-779.
[86] Zhao YD, Courtman DW, Deng Y, et al. Rescue of monocrotaline-induced pulmonary arterial hypertension using bone marrow-derived endothelial-like progenitor cells:efficacy of combined cell and eNOS gene therapy in established disease[J]. Circ Res, 2005, 96:442-450.
[87] Umar S, de Visser YP, Steendijk P, et al. Allogenic stem cell therapy improves right ventricular function by improving lung pathology in rats with pulmonary hypertension[J]. Am J Physiol Heart Circ Physiol, 2009, 297:H1606-H1616.
[88] Kanki-Horimoto S, Horimoto H, Mieno S, et al. Implantation of mesenchymal stem cells overexpressing endothelial nitric oxide synthase improves right ventricular impairments caused by pulmonary hypertension[J]. Circulation, 2006, 114:I181-I185.
[89] Baber SR, Deng W, Master RG, et al. Intratracheal mesenchymal stem cell administration attenuates monocrotaline-induced pulmonary hypertension and endothelial dysfunction[J]. Am J Physiol Heart Circ Physiol, 2007, 292:H1120-H1128.
[90] Luo L, Zheng W, Lian G, et al. Combination treatment of adipose-derived stem cells and adiponectin attenuates pulmonary arterial hypertension in rats by inhibiting pulmonary arterial smooth muscle cell proliferation and regulating the AMPK/BMP/Smad pathway[J]. Int J Mol Med, 2018, 41:51-60.
[91] Campbell AI, Zhao Y, Sandhu R, et al. Cell-based gene transfer of vascular endothelial growth factor attenuates monocrotaline-induced pulmonary hypertension[J]. Circulation, 2001, 104:2242-2248.
[92] Xiao Q, Li X, Li Y, et al. Biological drug and drug delivery-mediated immunotherapy[J]. Acta Pharm Sin B, 2020. DOI:10.1016/j.apsb.2020.12.018.
[93] Teng C, Lin C, Huang F, et al. Intracellular codelivery of anti-inflammatory drug and anti-miR 155 to treat inflammatory disease[J]. Acta Pharm Sin B, 2020, 10:1521-1533.
[94] Du X, Hou Y, Huang J, et al. Cytosolic delivery of the immunological adjuvant poly I:C and cytotoxic drug crystals via a carrier-free strategy significantly amplifies immune response[J]. Acta Pharm Sin B, 2021. DOI:10.1016/j.apsb.2021.03.014.
[95] He W, Xing X, Wang X, et al. Nanocarrier-mediated cytosolic delivery of biopharmaceuticals[J]. Adv Funct Mater, 2020, 30:1910566.
[96] He W, Kapate N, Shields IVCW, et al. Drug delivery to macrophages:a review of targeting drugs and drug carriers to macrophages for inflammatory diseases[J]. Adv Drug Deliv Rev, 2020, 165-166:15-40.