Receptor-mediated targeted drug delivery systems for treatment of inflammatory bowel disease: Opportunities and emerging strategies.

Acta Pharmaceutica Sinica B 2021;11(9):2798e2818 Chinese Pharmaceutical Association Institute of Materia Medica, Chinese Academy of Medical Sciences Acta Pharmaceutica Sinica B w w w. e l s ev i e r. c o m / l o c a t e / a p s b w w w. s c i e n c e d i r e c t . c o m REVIEW Receptor-mediated targeted drug delivery systems for treatment of inflammatory bowel disease: Opportunities and emerging strategies Peng Liua, Caifang Gaoa, Hongguo Chena, Chi Teng Vonga, Xu Wub, Xudong Tangc, Shengpeng Wanga,*, Yitao Wanga,* a State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China b Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, China c Department of Gastroenterology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China Received 18 August 2020; received in revised form 1 October 2020; accepted 14 October 2020 KEY WORDS Receptor-mediated target; Inflammatory bowel disease; Crohn’s disease; Ulcerative colitis; Drug delivery; Cell adhesion molecule; Abstract Inflammatory bowel disease (IBD) is a chronic intestinal disease with painful clinical manifestations and high risks of cancerization. With no curative therapy for IBD at present, the development of effective therapeutics is highly advocated. Drug delivery systems have been extensively studied to transmit therapeutics to inflamed colon sites through the enhanced permeability and retention (EPR) effect caused by the inflammation. However, the drug still could not achieve effective concentration value that merely utilized on EPR effect and display better therapeutic efficacy in the inflamed region because of nontargeted drug release. Substantial researches have shown that some specific receptors and cell adhesion molecules highly expresses on the surface of colonic endothelial and/or immune cells when IBD occurs, ligand- Abbreviations: ACQ, aggregation-caused quenching; ADR, adverse drug reaction; AIE, aggregation-induced emission; BSA, bovine serum albumin; CAM, cell adhesion molecule; CD, Crohn’s disease; CRD, cysteine-rich domain; CS, chondroitin sulfate; CT, computed tomography; CTLD, c-type lectinlike domain; DCs, dendritic cells; DSS, dextran sulfate sodium salt; EGF, epidermal growth factor; EPR, enhanced permeability and retention; FNII, fibronectin type II domain; FR, folate receptor; FRET, fluorescence resonance energy transfer; GIT, gastrointestinal tract; HA, hyaluronic acid; HUVEC, human umbilical vein endothelial cells; IBD, inflammatory bowel disease; ICAM, intercellular adhesion molecule; LMWC, low molecular weight chitosan; LPS, lipopolysaccharide; MAP4K4, mitogen-activated protein kinase kinase kinase kinase 4; MGL, macrophage galactose lectin; MPO, myeloperoxidase; MR, mannose receptor; MRI, magnetic resonance imaging; MPS, mononuclear phagocyte system; PAMAM, poly(amidoamine); PepT1, peptide transporter 1; PEI, polyethylenimine; PSGL-1, P-selectin glycoprotein ligand-1; QDs, quantum dots; RES, reticuloendothelial system; TfR, transferrin receptor; UC, ulcerative colitis; VCAM, vascular cell adhesion molecule. *Corresponding authors. Tel./fax: þ853 88228559 (Shengpeng Wang); Tel./fax: þ853 88224691 (Yitao Wang). E-mail addresses: (Shengpeng Wang), (Yitao Wang). Peer review under responsibility of Institute of Materia Medica, Chinese Academy of Medical Sciences and Chinese Pharmaceutical Association. https://doi.org/10.1016/j.apsb.2020.11.003 2211-3835 ª 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Receptor-mediated targeted drug delivery systems for treatment of IBD Active target; Targeted therapy 2799 modified drug delivery systems targeting such receptors and cell adhesion molecules can specifically deliver drug into inflamed sites and obtain great curative effects. This review introduces the overexpressed receptors and cell adhesion molecules in inflamed colon sites and retrospects the drug delivery systems functionalized by related ligands. Finally, challenges and future directions in this field are presented to advance the development of the receptor-mediated targeted drug delivery systems for the therapy of IBD. ª 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 1. Introduction Inflammatory bowel disease (IBD), comprised of Crohn’s disease (CD) and ulcerative colitis (UC), is characterized by chronic inflammation in the intestine1. Patients with IBD may suffer from abdominal pain, rectal bleeding, serious diarrhea, fever, weight loss, anemia and 2-fold higher risk of fatal colorectal cancer relative to healthy populations2,3. IBD possesses the highest prevalence with 0.3% in Western counties in 2017, and its incidence is increasing year by year worldwide4,5. To date, the exact etiology of IBD still remains unknown, however, it is wellaccepted that environmental factors, genetic predeposition, gut microbiota, and immune function dysregulation participate in the occurrence and development of IBD6. Conventional medications, including antibiotics, aminosalicylates, corticosteroids, immunomodulators, and monoclonal antibodies, have been applied for achieving and prolonging clinical remission, reducing surgical intervention and improving the quality of life7. But prolonged and systemic administration of such therapeutics could lead to heavy economic burden and/or serious adverse drug reaction (ADR), like superinfection, anaphylaxis, myelosuppression, gastrointestinal reaction, and osteoporosis7. One of the principal challenges in the therapeutic strategies of IBD is delivering therapeutics specifically to colonic inflammation regions. Conventional colon targeted drug delivery systems are generally designed to release drugs based on the traditional cognition about gastrointestinal pH, transit time, enzyme, and microbiome in the colon. However, the changes of gastrointestinal pH, transit time, enzyme and microbiome are unclear in the development of IBD, which results in aimless drug release, unsatisfactory therapeutic efficacy and enhanced ADR8. In recent years, novel nanocarriers, like liposome9, nanoparticle10, hydrogel11, dentrimer12, have received substantial attention and investigation due to their excellent physicochemical properties. The tissue permeability is increased in the inflamed colon, due to destroyed intestinal tight junction, the loss of cellular integrity and the infiltration of immune cells caused by inflammatory cytokines. Exploiting the leaky intestine, (...truncated)