Compositions and methods for drug delivery
A technology of polymers and cross-linked polymers, applied in drug delivery, pharmaceutical formulations, nano-medicines, etc., can solve problems such as low efficiency, and achieve the effects of enhanced stability, significant efficiency, and low toxicity
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Embodiment 1
[0262] Example 1: Complex Delivery of Blood-Brain Barrier (BBB) Penetrating Protein Nanoparticles to the Central Nervous System
[0263] Horseradish peroxide was first coupled with N-acryloyloxysuccinimide (NAS) to attach acryloyl groups to its surface. The average number of acryloyl groups conjugated to protein molecules was determined to be approximately 4.5 by measuring the residual (unreacted) lysines on the protein molecules with the fluorescamine assay.
[0264] After acryloyloxylation, the protein is encapsulated using an in situ polymerization method. MPC and the crosslinker bis-methacrylamide (BIS) were first prepared as 40% (m / v) stock solutions in deionized water and 10% (m / v) in anhydrous DMSO, respectively. MPC and BIS were then encapsulated into HRP protein (1 mg / mL) solution at a molar ratio of 5000:1 (MPC to HRP protein) and 500:1 (BIS to HRP protein), respectively. Polymerization was initiated by adding APS (300:1) and TEMED (1200:1) and maintained at 4°C ...
Embodiment 2
[0266] Example 2: Delivery of Therapeutic Proteins to the Central Nervous System (CNS) of Monkeys
[0267] Nimotuzumab protein can be directly encapsulated by in situ polymerization without acrylation reaction. Take MPC as a monomer. Poly(DL-lactide)-b-poly(ethylene glycol)-b-poly(DL-lactide)-diacrylic acid triblock copolymer (PLA-PEG-PLA diac) and glycerol dimethacrylate Esters (GDMA) were used as degradable crosslinkers. MPC, PLA-PEG-PLA copolymer and GDMA were added to the Nimotuzumab protein solution (2.2 mg / mL) and 500:1 (from GDMA to protein). Polymerization was initiated by adding APS (2000:1 ) and TEMED (8000:1 ) at 4°C for 3 hours. After polymerization, the solution was concentrated using a centrifugal filter unit to remove unreacted monomer and by-products. The protein nanoparticles were further purified with a hydrophobic interaction column (Phenyl-Sepharose CL-4B) to remove unencapsulated proteins.
[0268] To assess the efficiency of CNS delivery, Nimotuzuma...
Embodiment 3
[0269] Example 3: Treatment of brain tumors in mice
[0270] Nanoparticles of nimotuzumab (n(Nimotuzumab)) were synthesized using MPC and a peptide cross-linker with the amino acid sequence of VPLGVRTK, which can be degraded by tumor proteases.
[0271] Nimotuzumab solution (5 mg / mL) was diluted to 1 mg / mL with phosphate buffer (20 mM, pH=7.4) under ice bath. N-(3-aminopropyl)methacrylamide (APm) prepared in a 100 mg / mL aqueous solution was added to the protein solution and stirred at 4 °C for 10 min. APm is enriched around nimotumumab through electrostatic and hydrophobic interactions. Under rapid stirring, 2-methacryloyloxyethylphosphorylcholine and bisacrylylated VPLGVRTK peptide were sequentially added to the protein solution. Adjust the molar ratio of MPC:APm:crosslinker to 50:5:1. By dissolving ammonium persulfate in deionized water (the molar ratio of total monomer is 1:10) and an equal volume of 10% (w / v) N,N,N',N'-tetramethylethylenediamine Addition to free radica...
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