Affinity-controlled protein encapsulation into sub-30 nm telodendrimer nanocarriers by multivalent and synergistic interactions

Abstract

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.

Riboflavin-containing telodendrimer nanocarriers for efficient doxorubicin delivery: High loading capacity, increased stability, and improved anticancer efficacy

“…[62, 63] DOX has a positively charged amine group, which should be able to migrate under electric field. Being stably loaded in a nanocarrier, DOX should be trapped in the loading well due to the size effects.…”

Telodendrimers: Promising Architectural Polymers for Drug Delivery

“…A multifunctional telodendrimer of composition, PEG-poly(lysine), was synthesized using selective couplings, where an amine of lysine moieties was reacted with (Fmoc)Lys(Fmoc)-OH, followed by the reaction of the other with, for example, Fmoc-Arg(Pbf)-OH [ 170 ]. Using this strategy, a library of telodendrimers with different hydrophobic (heptadecanoic acid, cholesterol, or d -α-tocopherol) and charged moieties (arginine, arginine 2 , lysine 2 , or oxalic acid 2 ) were synthesized.…”

Tunable Engineering of Heparinized Injectable Hydrogels for Affinity‐Based Sustained Delivery of Bioactive Factors

“…Among them, affinity‐based controlled delivery systems have emerged as attractive systems that circumvent the challenges associated with conventional hydrogels . In particular, affinity‐based systems are important for the delivery of water‐soluble bioactive factors, because they possess simple processing conditions for loading . As a result, the bioactive factors are able to bind with affinity ligands through ionic and hydrophobic interactions, as well as inhibit the initial burst and provide sustained release by attenuating diffusional control due to the transient interactions with the hydrogel network .…”

“…In particular, affinity‐based systems are important for the delivery of water‐soluble bioactive factors, because they possess simple processing conditions for loading . As a result, the bioactive factors are able to bind with affinity ligands through ionic and hydrophobic interactions, as well as inhibit the initial burst and provide sustained release by attenuating diffusional control due to the transient interactions with the hydrogel network . Sulfated polysaccharide derivatives can bind with various bioactive factors through affinity interactions, and they have been extensively studied for controlled release .…”