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Published on: June 13, 2014
pH-Ultrasensitive Membranolytic Polyesters with Alternating Sequence of Ionizable and Hydrophobic Groups for
Jihong Wang1,2, Yueling Yuan3,4, Chanjuan Su4
1School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou 511442, China.
Abstract:
Oncolytic therapy, inducing cell death via cell membrane lysis, holds considerable promise in cancer treatment. However, achieving precise control over the structure and function of oncolytic materials for highly selective oncolytic therapy is a key challenge in the context of the subtle differences between tumor and normal tissues/cells. Herein, we report the development of pH-ultrasensitive oncolytic polyesters (pOPs) with an alternating sequence of ionizable and hydrophobic groups. This design enables a refined "OFF" to "ON" switch within 0.2 pH units, ensuring high selectivity in membranolytic activity and cytotoxicity of pOPs between the pH levels of normal tissues and tumor acidity. The top-performing pOP, P(P-AC7), demonstrated a maximum tolerated dose of >100 mg kg-1 after intravenous administration and potent cytotoxicity at pH 6.8. Notably, the molecular weight of P(P-AC7) had a minimal effect on its pH-dependent cytotoxicity once the degree of polymerization was ≥49, ensuring consistency in properties across batches. P(P-AC7) exerts membranolytic activity by interacting with phosphatidylserine at pH 6.8 and shows high antitumor efficacy in various tumor models. Overall, we developed a strategy to develop oncolytic polymers with a precise structure for selective oncolytic therapy.
Insights
Researchers developed pH-ultrasensitive oncolytic polyesters (pOPs) for selective cancer therapy. These polymers precisely target tumor acidity, inducing cell death with minimal impact on healthy tissues.
Area of Science:
- Polymer Chemistry
- Nanomedicine
- Oncology
Background:
- Oncolytic therapy offers promise for cancer treatment by inducing cell death through membrane lysis.
- A significant challenge is achieving selectivity due to subtle differences between tumor and normal tissues.
- Precise control over oncolytic material structure and function is crucial for targeted therapy.
Purpose of the Study:
- To develop pH-ultrasensitive oncolytic polyesters (pOPs) for highly selective cancer therapy.
- To engineer pOPs with a tunable "OFF" to "ON" switch for targeted membranolytic activity.
- To evaluate the antitumor efficacy and safety of the developed pOPs.
Main Methods:
- Synthesized pOPs with an alternating sequence of ionizable and hydrophobic groups.
- Investigated the pH-dependent membranolytic activity and cytotoxicity of pOPs.
- Assessed the maximum tolerated dose and antitumor efficacy of the lead pOP in preclinical tumor models.
Main Results:
- Developed pOPs exhibiting a sharp pH switch (0.2 pH units) for selective activity.
- The lead pOP, P(P-AC7), showed potent cytotoxicity at tumor-associated pH 6.8 and high safety (>100 mg kg-1).
- Molecular weight had minimal impact on cytotoxicity for polymers with a degree of polymerization ≥49, ensuring batch consistency.
- P(P-AC7) demonstrated membranolytic activity via phosphatidylserine interaction and significant antitumor efficacy.
Conclusions:
- A strategy for creating precisely structured oncolytic polymers was established.
- pH-ultrasensitive pOPs offer a promising approach for selective oncolytic cancer therapy.
- The developed polymers exhibit tunable properties for enhanced therapeutic targeting and efficacy.
