Time-staggered delivery of docetaxel and H1-S6A,F8A peptide for sequential dual-strike chemotherapy through tumor priming and nuclear targeting.
While highly effective for slowing cancer progression in principle, the c-Myc inhibitor peptide H1-S6A,F8A (H1) has not performed well in tumor studies, in part because it does not pass efficiently through the nuclear envelope. Here we describe a dual-strike strategy in which tumor cells were treated first with N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-docetaxel (DTX) conjugates (P-DTX), which arrested cells in the G2/M phase and prolonged the period when the nuclear membrane was disassembled. In the second strike, the cells were then treated with P-H1 conjugates, which entered the nucleus and efficiently inhibited c-Myc. The in vitro studies demonstrated that the combination of P-DTX and P-H1 conjugates was sequence-dependent, and P-DTX followed by P-H1 had synergism, which was significantly more effective than reverse sequential delivery, simultaneous co-delivery or monotherapy with P-DTX or P-H1 alone. The in vivo studies showed that sequential delivery of P-DTX followed by P-H1 remarkably slowed the tumor growth and improved the animal survival. This sequential, dual-strike approach provides new opportunities for nuclear-targeted anticancer drug delivery.
Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, PR China.
Lian
L
Li
Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, PR China.
Wei
W
Sun
Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, PR China.
Zhirong
Z
Zhang
Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, PR China. Electronic address: huangyuan0@163.com.
Yuan
Y
Huang
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000077143:Docetaxel; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D011109:Polymethacrylic Acids / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000378:metabolism; D043823:Taxoids / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D047368:Tumor Burden / Q000187:drug effects
D000970:Antineoplastic Agents; D010455:Peptides; D011109:Polymethacrylic Acids; D016271:Proto-Oncogene Proteins c-myc; D043823:Taxoids; D000077143:Docetaxel; C011533:Duxon
Combinatory therapy; HPMA copolymers; Nuclear delivery; Sequential treatment; Synergistic effect