Related Experiment Video
Updated: May 3, 2026
An Orthotopic Bladder Tumor Model and the Evaluation of Intravesical saRNA Treatment
Published on: July 28, 2012
Tumor priming enhances siRNA delivery and transfection in intraperitoneal tumors
Jie Wang1, Ze Lu1, Bertrand Z Yeung2
1Optimum Therapeutics LLC, 9363 Towne Centre Drive, Suite 110, San Diego 92121, USA.
Abstract:
Cancers originating from the digestive system account for 290,000 or ~20% of all new cancer cases annually in the US. We previously developed paclitaxel-loaded tumor-penetrating microparticles (TPM) for intraperitoneal (IP) treatment of peritoneal tumors (Lu et al., 2008; Tsai et al., 2007; Tsai et al., 2013). TPM is undergoing NIH-supported IND-enabling studies for clinical evaluation. The present study evaluated the hypothesis that TPM, via inducing apoptosis and expanding the interstitial space, promotes the delivery and transfection of lipid vectors containing siRNA. The in vivo model was the metastatic human Hs766T pancreatic tumor that, upon IP injection, produced widely distributed solid tumors and ascites in the peritoneal cavity in 100% of animals. The target gene was survivin, an anti-apoptotic protein induced by chemotherapy and associated with metastases and poor prognosis of patients with gastric and colorectal cancers. The siRNA carrier was pegylated liposomes comprising cationic and neutral lipids plus a fusogenic lipid (PCat). PCat-loaded with survivin siRNA (PCat-siSurvivin) was active in cultured cells (decreased survivin mRNA and protein levels, reduced cell clonogenicity, enhanced paclitaxel activity), but lost its activity in vivo; this difference is consistent with the well-known problem of inadequate delivery and transfection of siRNA in vivo. In comparison, single agent TPM prolonged animal survival and, as expected, induced survivin expression in tumors. Addition of PCat-siSurvivin reversed the TPM-induced survivin expression and enhanced the antitumor activity of TPM. The finding that in vivo survivin knockdown by PCat-siSurvivin was successful only when it was given in combination with TPM provides the proof-of-concept that tumor priming promotes the delivery and transfection of liposomal siRNA. The data further suggest the TPM/PCat-siSurvivin combination as a potentially useful chemo-gene therapy for peritoneal cancer.
Insights
Tumor-penetrating microparticles (TPM) enhance the delivery of survivin siRNA liposomes, improving chemo-gene therapy for peritoneal cancer. This combination therapy shows promise for treating metastatic pancreatic tumors.
Area of Science:
- Oncology
- Nanomedicine
- Gene Therapy
Background:
- Digestive system cancers represent ~20% of US cancer cases.
- Paclitaxel-loaded tumor-penetrating microparticles (TPM) were developed for intraperitoneal treatment of peritoneal tumors.
- Inadequate delivery and transfection of in vivo siRNA limits its therapeutic potential.
Purpose of the Study:
- To evaluate if TPM enhances the delivery and transfection of liposomal survivin siRNA.
- To test the hypothesis that TPM promotes apoptosis and expands the interstitial space for improved siRNA delivery.
- To assess the combination therapy of TPM and survivin siRNA for peritoneal cancer treatment.
Main Methods:
- Utilized a metastatic human Hs766T pancreatic tumor xenograft model in mice.
- Administered intraperitoneally paclitaxel-loaded tumor-penetrating microparticles (TPM) and pegylated liposomes with survivin siRNA (PCat-siSurvivin).
- Assessed tumor growth, survivin expression, apoptosis, and animal survival.
Main Results:
- Single-agent TPM prolonged survival and increased tumor survivin expression.
- PCat-siSurvivin alone showed limited in vivo activity.
- Combination therapy (TPM + PCat-siSurvivin) reversed TPM-induced survivin upregulation and enhanced antitumor activity, demonstrating successful in vivo survivin knockdown.
Conclusions:
- Tumor priming with TPM facilitates the delivery and transfection of liposomal siRNA.
- The combination of TPM and PCat-siSurvivin provides a proof-of-concept for chemo-gene therapy in peritoneal cancer.
- This combination therapy holds potential for treating peritoneal cancers, including metastatic pancreatic tumors.
