PMID- 30214200 OWN - NLM STAT- MEDLINE DCOM- 20181022 LR - 20220408 IS - 1178-2013 (Electronic) IS - 1176-9114 (Print) IS - 1176-9114 (Linking) VI - 13 DP - 2018 TI - Anti-EGFR-iRGD recombinant protein modified biomimetic nanoparticles loaded with gambogic acid to enhance targeting and antitumor ability in colorectal cancer treatment. PG - 4961-4975 LID - 10.2147/IJN.S170148 [doi] AB - BACKGROUND: Red blood cell membrane-coated nanoparticle (RBCm-NP) platform, which consist of natural RBCm and synthetic polymeric core, can extend circulation time in vivo with an improved biocompatibility and stability of this biomimetic nanocarrier. To achieve better bioavailability of antitumor drugs that were loaded in RBCm-NPs, the functionalization of coated RBCm with specific targeting ability is essential. Bispecific recombinant protein anti-EGFR-iRGD, containing both tumor penetrating peptide (internalizing RGD peptide) and EGFR single-domain antibody (sdAb), seems to be an optimal targeting ligand for RBCm-NPs in the treatment of multiple tumors, especially colorectal cancer with high EGFR expression. MATERIALS AND METHODS: We modified the anti-EGFR-iRGD recombinant protein on the surface of RBCm-NPs by lipid insertion method to construct iE-RBCm-PLGA NPs and confirmed the presentation of active tumor-targeting ability in colorectal cancer models with high EGFR expression when compared with RBCm-PLGA NPs. In addition, potential anti-tumor drug gambogic acid (GA) was loaded into the NPs to endow the antitumor efficiency of iE-RBCm-GA/PLGA NPs. It was simultaneously evaluated whether GA can reach better biocompatibility benefiting from the improved antitumor efficiency of iE-RBCm-GA/PLGA NPs in colorectal cancer models. RESULTS: We successfully modified anti-EGFR-iRGD proteins on the surface of biomimetic NPs with integrated and stable "shell-core" structure. iE-RBCm-PLGA NPs showed its improved targeting ability in vitro (multicellular spheroids [MCS]) and in vivo (nude mice bearing tumors). Besides, no matter on short-term cell apoptosis at tumor site (terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling [TUNEL]) and long-term tumor inhibition, iE-RBCm-GA/PLGA NPs achieved better antitumor efficacy than free GA in spite of the similar effects of cytotoxicity and apoptosis to GA in vitro. CONCLUSION: We expect that the bispecific biomimetic nanocarrier can extend the clinical application of many other potential antitumor drugs similar to GA and become a novel drug carrier in the colorectal cancer treatment. FAU - Zhang, Zhen AU - Zhang Z AD - Comprehensive Cancer Center, Nanjing Drum Tower Hospital, Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu, People's Republic of China, xiaopingqian@nju.edu.cn. AD - Department of Integrated Traditional Chinese Medicine and Western Medicine Oncology, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, People's Republic of China. FAU - Qian, Hanqing AU - Qian H AD - Comprehensive Cancer Center, Nanjing Drum Tower Hospital, Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu, People's Republic of China, xiaopingqian@nju.edu.cn. FAU - Huang, Jie AU - Huang J AD - Comprehensive Cancer Center, Nanjing Drum Tower Hospital, Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu, People's Republic of China, xiaopingqian@nju.edu.cn. FAU - Sha, Huizi AU - Sha H AD - Comprehensive Cancer Center, Nanjing Drum Tower Hospital, Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu, People's Republic of China, xiaopingqian@nju.edu.cn. FAU - Zhang, Hang AU - Zhang H AD - Comprehensive Cancer Center, Nanjing Drum Tower Hospital, Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu, People's Republic of China, xiaopingqian@nju.edu.cn. FAU - Yu, Lixia AU - Yu L AD - Comprehensive Cancer Center, Nanjing Drum Tower Hospital, Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu, People's Republic of China, xiaopingqian@nju.edu.cn. FAU - Liu, Baorui AU - Liu B AD - Comprehensive Cancer Center, Nanjing Drum Tower Hospital, Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu, People's Republic of China, xiaopingqian@nju.edu.cn. FAU - Hua, Dong AU - Hua D AD - Department of Medical Oncology, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, People's Republic of China, huadong_jnu@163.com. FAU - Qian, Xiaoping AU - Qian X AD - Comprehensive Cancer Center, Nanjing Drum Tower Hospital, Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu, People's Republic of China, xiaopingqian@nju.edu.cn. LA - eng PT - Journal Article DEP - 20180831 PL - New Zealand TA - Int J Nanomedicine JT - International journal of nanomedicine JID - 101263847 RN - 0 (Antineoplastic Agents) RN - 0 (Drug Carriers) RN - 0 (Lipids) RN - 0 (N-end cysteine peptide tumor-homing peptide) RN - 0 (Oligopeptides) RN - 0 (Recombinant Proteins) RN - 0 (Xanthones) RN - 1SIA8062RS (Polylactic Acid-Polyglycolic Acid Copolymer) RN - 26009-03-0 (Polyglycolic Acid) RN - 33X04XA5AT (Lactic Acid) RN - 8N585K83U2 (gambogic acid) RN - EC 2.7.10.1 (ErbB Receptors) SB - IM MH - Animals MH - Antineoplastic Agents/pharmacology/*therapeutic use MH - Apoptosis/drug effects MH - Biomimetic Materials/*chemistry MH - Cell Line, Tumor MH - Cell Proliferation/drug effects MH - Colorectal Neoplasms/*drug therapy/pathology MH - Drug Carriers/chemistry MH - ErbB Receptors/*antagonists & inhibitors/metabolism MH - Humans MH - Lactic Acid/chemistry MH - Lipids MH - Mice, Inbred BALB C MH - Mice, Nude MH - Nanoparticles/*chemistry/ultrastructure MH - Oligopeptides/*chemistry MH - Polyglycolic Acid/chemistry MH - Polylactic Acid-Polyglycolic Acid Copolymer MH - Recombinant Proteins/*chemistry MH - Xanthones/pharmacology/*therapeutic use PMC - PMC6124475 OTO - NOTNLM OT - anti-EGFR-iRGD recombinant protein OT - antitumor efficiency OT - biomimetic nanocarrier OT - colorectal cancer OT - gambogic acid OT - targeting ability COIS- Disclosure The authors report no conflicts of interest in this work. EDAT- 2018/09/15 06:00 MHDA- 2018/10/23 06:00 PMCR- 2018/08/31 CRDT- 2018/09/15 06:00 PHST- 2018/09/15 06:00 [entrez] PHST- 2018/09/15 06:00 [pubmed] PHST- 2018/10/23 06:00 [medline] PHST- 2018/08/31 00:00 [pmc-release] AID - ijn-13-4961 [pii] AID - 10.2147/IJN.S170148 [doi] PST - epublish SO - Int J Nanomedicine. 2018 Aug 31;13:4961-4975. doi: 10.2147/IJN.S170148. eCollection 2018.