Novel nanocarriers are highly demanded for the delivery of heterogeneous protein therapeutics for disease treatments. Conventional nanoparticles for protein delivery are mostly based on the diffusion-limiting mechanisms, e.g., physical trapping and entanglement. We develop herein a novel linear-dendritic copolymer (named telodendrimer) nanocarrier for efficient protein delivery by affinitive coating. This affinity-controlled encapsulation strategy provides nanoformulations with a small particle size (<30 nm), superior loading capacity (>50% w/w) and maintained protein bioactivity. We integrate multivalent electrostatic and hydrophobic functionalities synergistically into the well-defined telodendrimer scaffold to fine-tune protein binding affinity and delivery properties. The ion strength and density of the charged groups as well as the structure of the hydrophobic segments are important and their combinations in telodendrimers are crucial for efficient protein encapsulation. We have conducted a series of studies to understand the mechanism and kinetic process of the protein loading and release, utilizing electrophoresis, isothermal titration calorimetry, Förster resonance energy transfer spectroscopy, bio-layer interferometry and computational methods. The optimized nanocarriers are able to deliver cell-impermeable therapeutic protein intracellularly to kill cancer cells efficiently. In vivo imaging studies revealed cargo proteins preferentially accumulate in subcutaneous tumors and retention of peptide therapeutics is improved in an orthotopic brain tumor, these properties are evidence of the improved pharmacokinetics and biodistributions of protein therapeutics delivered by telodendrimer nanoparticles. This study presents a bottom-up strategy to rationally design and fabricate versatile nanocarriers for encapsulation and delivery of proteins for numerous applications.

Certain natural products such as gambogic acid (GA) exhibit potent antitumor effects. Unfortunately, administration of these natural products is limited by their poor solubility in conventional pharmaceutical solvents. In this study, a series of telodendrimers, composed of linear polyethylene glycol (PEG)-blocking-dendritic oligomer of cholic acid (CA) and vitamin E (VE), have been designed with architectures optimized for efficient delivery of GA and other natural anticancer compounds. Two of the telodendrimers with segregated CA and VE domains self-assembled into stable cylindrical and/or spherical nanoparticles (NPs) after being loaded with GA as observed under transmission electron microscopy (TEM), which correlated with the dynamic light scattering (DLS) analysis of sub-30 nm particle sizes. A very high GA loading capacity (3:10 drug/polymer w/w) and sustained drug release were achieved with the optimized telodendrimers. These novel nanoformulations of GA were found to exhibit similar in vitro cytotoxic activity against colon cancer cells as the free drug. Near-infrared fluorescence small animal imaging revealed preferential accumulation of GA-loaded NPs into tumor tissue. The optimized nanoformulation of GA achieved superior antitumor efficacy compared to GA-Cremophor EL formulation at equivalent doses in HT-29 human colon cancer xenograft mouse models. Given the mild adverse effects associated with this natural compound and the enhanced anticancer effects via tumor targeted telodendrimer delivery, the optimized GA nanoformulation is a promising alternative to the traditional chemotherapy in colon cancer treatment.

A strategy to precisely engineer lipidoid‐telodendrimer binary hybrid nanoparticles that offer enhanced cell membrane permeability for therapeutic proteins to reach the intracellular targets is established. The highly controllable biochemical and physical properties of the nanoparticles make them promising for protein‐based brain cancer treatment with the assistance of convection‐enhanced delivery.

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