Effective Delivery of PEGylated siRNA-Containing Lipoplexes to Extraperitoneal Tumours following Intraperitoneal
Akul Singhania1, Sherry Y Wu, Nigel A J McMillan
1The University of Queensland Diamantina Institute, Princess Alexandra Hospital, The University of Queensland, Woolloongabba, QLD 4102, Australia.
Abstract:
Intraperitoneal (i.p.) administration of small interfering RNA (siRNA) has, to date, shown promise in treating tumours located within the peritoneal cavity. The ability of these siRNA molecules to reach extraperitoneal tumours following i.p. administration is, however, yet to be investigated. Here, we examined the impact of PEGylation on the biodistribution of i.p. administered nucleic acids-containing lipoplexes. We showed that in contrast to non-PEGylated liposomes, PEGylated liposomes can deliver siRNA efficiently to extraperitoneal tumours following i.p. administration, resulting in a 45% reduction in tumour size when the oncogene-targeted siRNA was used. This difference was likely contributed by the decreased uptake of PEGylated lipoplexes in the first-pass organs, and, in particular, we observed a 10-fold decrease in the macrophage uptake of these particles compared to non-PEGylated counterparts. Overall, our results indicated the potential of using PEGylated liposomes to deliver siRNA for the treatment of i.p. localized cancer with coexisting extraperitoneal metastasis.
Insights
PEGylated liposomes effectively deliver small interfering RNA (siRNA) to extraperitoneal tumors after intraperitoneal administration, significantly reducing tumor size. This advancement offers new hope for treating localized cancers with distant metastases.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Intraperitoneal (i.p.) administration of small interfering RNA (siRNA) shows promise for peritoneal tumors.
- The efficacy of i.p. delivered siRNA for extraperitoneal tumors remains largely uninvestigated.
Purpose of the Study:
- To evaluate the impact of PEGylation on the biodistribution of siRNA-loaded lipoplexes following i.p. administration.
- To determine if PEGylated liposomes can enhance siRNA delivery to extraperitoneal tumors.
Main Methods:
- Comparison of PEGylated versus non-PEGylated liposomes for siRNA delivery after i.p. injection.
- Assessment of lipoplex biodistribution and tumor targeting in a preclinical cancer model.
- Quantification of macrophage uptake of lipoplexes in first-pass organs.
Main Results:
- PEGylated liposomes efficiently delivered siRNA to extraperitoneal tumors, unlike non-PEGylated liposomes.
- Treatment with PEGylated liposomes resulted in a 45% reduction in tumor size when using oncogene-targeted siRNA.
- PEGylated lipoplexes exhibited a 10-fold decrease in macrophage uptake compared to non-PEGylated counterparts, suggesting reduced clearance.
Conclusions:
- PEGylation enhances the delivery of i.p. administered siRNA to extraperitoneal tumors.
- PEGylated liposomes represent a promising strategy for treating intraperitoneal cancers with extraperitoneal metastasis.
- Reduced uptake by macrophages in first-pass organs contributes to the improved biodistribution of PEGylated liposomes.
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