Paclitaxel tumor priming promotes delivery and transfection of intravenous lipid-siRNA in pancreatic tumors.
The major barrier for using small interfering RNA (siRNA) as cancer therapeutics is the inadequate delivery and transfection in solid tumors. We have previously shown that paclitaxel tumor priming, by inducing apoptosis, expands the tumor interstitial space, improves the penetration and dispersion of nanoparticles and siRNA-lipoplexes in 3-dimensional tumor histocultures, and promotes the delivery and transfection efficiency of siRNA-lipoplexes under the locoregional setting in vivo (i.e., intraperitoneal treatment of intraperitoneal tumors). The current study evaluated whether tumor priming is functional for systemically delivered siRNA via intravenous injection, which would subject siRNA to several additional delivery barriers and elimination processes. We used the same pegylated cationic (PCat)-siRNA lipoplexes as in the intraperitoneal study to treat mice bearing subcutaneous human pancreatic Hs766T xenograft tumors. The target gene was survivin, an inducible chemoresistance gene. The results show single agent paclitaxel delayed tumor growth but also significantly induced the survivin protein level in residual tumors, whereas addition of PCat-siSurvivin completely reversed the paclitaxel-induced survivin and enhanced the paclitaxel activity (p<0.05). In comparison, PCat-siSurvivin alone did not yield survivin knockdown or antitumor activity, indicating the in vivo effectiveness of intravenous siRNA-mediated gene silencing requires paclitaxel cotreatment. Additional in vitro studies showed that paclitaxel promoted the cytoplasmic release of siGLO, a 22 nucleotide double-stranded RNA that has no mRNA targets, from its PCat lipoplex and/or endosomes/lysosomes. Taken together, our earlier and current data show paclitaxel tumor priming, by promoting the interstitial transport and cytoplasmic release, is critical to promote the delivery and transfection of siRNA in vivo. In addition, because paclitaxel has broad spectrum activity and is used to treat multiple types of solid tumors including the hard-to-treat pancreatic cancer, the synergistic paclitaxel+siSurvivin combination represents a potentially useful chemo-gene therapy.
Optimum Therapeutics LLC, 1815 Aston Avenue, STE 107, Carlsbad, CA 92008, USA.
Jie
J
Wang
Optimum Therapeutics LLC, 1815 Aston Avenue, STE 107, Carlsbad, CA 92008, USA.
Ze
Z
Lu
Optimum Therapeutics LLC, 1815 Aston Avenue, STE 107, Carlsbad, CA 92008, USA.
Junfeng
J
Wang
Optimum Therapeutics LLC, 1815 Aston Avenue, STE 107, Carlsbad, CA 92008, USA.
Minjian
M
Cui
Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73014, USA.
Bertrand Z
BZ
Yeung
Medical University of South Carolina, Charleston, SC 29425, USA.
David J
DJ
Cole
Optimum Therapeutics LLC, 1815 Aston Avenue, STE 107, Carlsbad, CA 92008, USA.
M Guillaume
MG
Wientjes
Optimum Therapeutics LLC, 1815 Aston Avenue, STE 107, Carlsbad, CA 92008, USA; Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73014, USA; Medical University of South Carolina, Charleston, SC 29425, USA; Taipei Medical University, Taipei, Taiwan, ROC. Electronic address: jau@optimumtx.com.
Jessie L-S
JL
Au
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D005260:Female; D020868:Gene Silencing / Q000187:drug effects; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000187:drug effects; D007275:Injections, Intravenous; D008055:Lipids / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D017239:Paclitaxel / Q000008:administration & dosage* / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000628:therapy*; D010534:Peritoneal Neoplasms / Q000188:drug therapy; D012334:RNA, Neoplasm / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000494:pharmacology*; D000077022:Survivin; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008055:Lipids; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D000077022:Survivin; D017239:Paclitaxel
Chemo-gene therapy; Intravenous siRNA delivery; Paclitaxel; Pancreatic cancer; Survivin