Bottlebrush Polymer-Conjugated Melittin Exhibits Enhanced Antitumor Activity and Better Safety Profile
Improved PEGylated polymer system for ultra-shielding anti-cancer cargo demonstrating increased safety while maintaining functional pharmacodynamics
Institute Reference: INV-21037
Cancer remains one of the leading causes of death worldwide. Treatments have significantly improved over the past decade, yet many challenges still remain with targeting, delivery and biological variability between cancer types. One popular strategy of treating a variety of different cancer types is harnessing the immense power of the flexibility and diversity of naturally toxic peptides found in poisons and venoms. Over 7,000 natural peptides with various activity including hormones, neurotransmitters, and growth factors, have been discovered leading to more than 80 drugs on the market and over 150 candidates in various stages of clinical trial. These peptides demonstrate natural anti-bacterial, anti-viral, and anti-cancer effects. The problem with many of these peptides lies in delivery, naturally low protease function, rapid renal clearance, and major unintended off-target effects. Here the inventors developed a polymer system that can enhance the biopharmaceutical properties of therapeutic peptides. Using a model system of a powerful potential therapeutic, melittin (a bee venom peptide), they demonstrate that the polymer greatly reduces non-specific toxic effects of the peptide while enhancing plasma pharmacokinetics, passive tumor accumulation, and tumor-specific toxicity. This unique polymer system could be broadly applicable to a variety of therapeutic candidates targeting multiple cancers and beyond.
Northeastern inventors have constructed a biohybrid involving bottlebrush PEG and melittin (MEL), termed pacMEL. This model system utilized a natural venom peptide as a model to describe the potential of bottlebrush PEG in the delivery of various anti-microbial, anti-viral and anti-cancer agents. Native, unshielded MEL has been studied in few early-stage clinical trials due to its potent toxicity and has not been pursued further due to its susceptibility to degradation and widespread negative side effects. Conventional PEGylation with its more linear structure does not overcome various toxicities due to incomplete shielding of MEL and demonstrates limited pharmacodynamics. This unique polymer system has a more complex, high-density, branching arrangement which improves the steric inhibition against protease degradation, enhances plasma pharmacokinetics and significantly reduces hepatic damage and immunogenicity. In an initial in vivo mouse xenograft model, pacMEL’s increased protection of its internal peptide cargo and increased PK/PD allows for significant accumulation in tumor sites where the microenvironment will support the release of the active compound or pacMEL will be endocytosed to enact its anti-tumor effects. Despite the high anti-tumor effect seen in this model, there was no increase in off-targets such as hepatic damage, coagulopathy, or hemolysis. pacMEL fully retained the incredible intended apoptotic/necrotic potency of MEL while significantly diminishing any negative effects seen with MEL alone.
The proposed delivery platform is based on a single-entity bottlebrush polymer. This unimolecular design can provide high consistency in manufacturing processes.
The single-entity bottlebrush polymer allows storage under ambient conditions while maintaining efficacy. Current lipid-based delivery systems require specific temperature-controlled conditions for shipping and storage.
Bottlebrush-architecture PEG offers substantially greater steric protection and prolonged plasma pharmacokinetics compared to traditional linear-based systems.
More complete shielding of internal cargo (i.e., melittin) within the bottlebrush polymer leads to a significant reduction in side effects associated with cargo, such as hemolysis, anti-coagulation, hepatic damage, and immune system stimulation.
The polymer improves blood circulation times of the peptide, reduces liver uptake, and improves tumor-specific toxicity in a mouse model.
A bioreductively cleavable disulfide linker between target peptides and vectors allows the release of peptides inside of the tumor cells.
Delivery of melittin or therapeutic peptides (microbicides, virucides, fungicides, tumoricidal).
The delivery vehicle for small molecule drugs with narrow therapeutic indices.
Delivery of nucleic acids (mRNA vaccines, cancer vaccines, gene editing).
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