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Highly stable polyglutamate derivatives/siRNA polyplex efficiently down-relegate survivin expression and augment the
Zhongjuan Wang1, Haijuan Zou1, Zirui Wang1
1Department of Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, University Town, Guangzhou 510006, PR China.
Abstract:
RNA interfere (RNAi)-based technology holds great promise in cancer treatment. The use of small interfering RNA (siRNA), however, is hampered by its low delivery efficiency in vivo when they are diluted in blood biofluids and in the presence of serum and salt. In this study, we developed the polyglutamate derivative polymer brush, poly(ethyleneglycol) monomethyl ether-b-polyglutamate-g-spermine (mPEG-b-PG-g-spermine, PPGS), which could efficiently deliver survivin-siRNA under ultra-high dilution and in the presence of salt (NaCl 150mM) and serum (10% FBS), most likely due to its PEG-shelled polymer brush structure. On the contrary, aggregation occurred when PEI/siRNA polyplex dispersed in saline and serum-containing media and PEI polyplex dissociated after making a 256-fold dilution. PPGS/si-survivin polyplex exhibited high cellular uptake efficiency and efficiently down-regulated the expression of survivin mRNA in the cisplatin-resistance of non-small cell human lung adenocarcinoma (A549/DDP) cells in the presence of serum. However, either PEI polyplex or Lipofectmine 2000 complex was unstable in serum and salt-containing media and at high dilution rates, which resulted in their dramatical decrease of cellular uptake and gene-silencing efficiency in these conditions. The PPGS/si-survivin polyplex also exhibited synergistic effects of killing the cancer cells by combination treatment with cisplatin. Therefore, the PPGS gene carrier showed great potential in systemic siRNA delivery, and its combination with chemotherapeutic drug is promising in treating drug resistant cancers.
Insights
A novel polymer brush, PPGS, efficiently delivers survivin-siRNA for cancer therapy, overcoming challenges of low delivery efficiency in blood. This approach shows promise for treating drug-resistant cancers when combined with chemotherapy.
Area of Science:
- Biotechnology
- Nanomedicine
- Cancer Research
Background:
- RNA interference (RNAi) using small interfering RNA (siRNA) is a promising cancer treatment strategy.
- In vivo siRNA delivery is limited by instability in blood, serum, and salt, reducing efficiency.
- Existing carriers like PEI and Lipofectamine 2000 show poor performance under these conditions.
Purpose of the Study:
- To develop a novel polymer carrier for efficient in vivo siRNA delivery.
- To evaluate the efficacy of the new carrier in overcoming delivery challenges posed by biological fluids.
- To assess the synergistic effect of the carrier combined with chemotherapy for drug-resistant cancers.
Main Methods:
- Synthesis of a polyglutamate derivative polymer brush: poly(ethyleneglycol) monomethyl ether-b-polyglutamate-g-spermine (mPEG-b-PG-g-spermine, PPGS).
- Complexation of PPGS with survivin-siRNA (PPGS/si-survivin polyplex).
- Evaluation of polyplex stability, cellular uptake, and gene silencing in A549/DDP cells under challenging conditions (high dilution, serum, salt).
- Assessment of synergistic anti-cancer effects with cisplatin.
Main Results:
- PPGS efficiently delivered survivin-siRNA even under ultra-high dilution, in 150mM NaCl, and 10% FBS, owing to its PEG-shelled brush structure.
- PEI/siRNA polyplexes aggregated and dissociated in saline and serum, showing significantly lower cellular uptake and gene silencing.
- PPGS/si-survivin polyplex demonstrated high cellular uptake and effectively down-regulated survivin mRNA in cisplatin-resistant lung cancer cells.
- The combination of PPGS/si-survivin polyplex and cisplatin showed synergistic cancer cell killing effects.
Conclusions:
- The PPGS polymer brush is a highly effective carrier for systemic siRNA delivery, overcoming common in vivo delivery barriers.
- PPGS-based siRNA delivery shows significant potential for treating drug-resistant cancers, especially when combined with chemotherapeutic agents like cisplatin.
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