Surface-modified nanoparticles for intracellular delivery of therapeutic agents and composition for making same
Inventors
Labhasetwar, Vinod • Vasir, Jaspreet
Assignees
National Institutes of Health NIH • University of Nebraska System • US Department of Health and Human Services
Publication Number
US-8865216-B2
Publication Date
2014-10-21
Expiration Date
2028-08-01
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Abstract
Surface-modified polymeric nanoparticles (NPs), compositions for making them, and their use in drug delivery are disclosed.
Core Innovation
The invention relates to surface-modified polymeric nanoparticles (NPs), their compositions, and their use in drug delivery. The surface modification involves a biocompatible polymer with a net negative surface charge at neutral pH, at least one charge modulator capable of reversing the surface charge from negative to positive in an acidic environment, and optionally, an amphiphilic emulsifier. This modification increases the force and occurrence of NP interactions with the cell membrane, improving the efficiency of intracellular delivery of therapeutic agents carried by the NPs, particularly facilitating cytoplasmic drug delivery.
The problem addressed is the limited understanding and lack of methodology for assessing nanocarrier interactions with cellular components and intracellular trafficking, which hinders the development of efficient nanocarriers for targeted drug delivery. Specifically, while polymeric NPs can undergo surface charge reversal in acidic endo-lysosomal environments facilitating cytosolic escape, only a small fraction escape efficiently, limiting intracellular delivery effectiveness. The invention aims to provide NPs with optimized surface charge reversal and increased affinity for cell membranes to enhance cellular uptake and intracellular delivery efficacy.
The invention further provides a method for making surface-modified NPs by forming a primary water-in-oil emulsion of bioactive agent and biocompatible polymer solution, mixing with an aqueous charge modulator solution and optional emulsifier to form a water-in-oil-in-water emulsion, removing organic solvent, and recovering the modified NPs. The charge modulator is disposed on the NP surface with functional groups available at the interface, enabling responsive modulation of surface properties such as charge in response to pH changes, thus improving interactions with cell membranes compared to unmodified NPs.
Claims Coverage
The patent includes five claims with one primary independent claim. The independent claim focuses on a specifically composed surface modified nanoparticle for therapeutic agent delivery.
Surface modified nanoparticle composition
A surface modified nanoparticle comprising (i) a biocompatible polymer poly(lactide-co-glycolide), (ii) an amphiphilic emulsifier polyvinyl alcohol, and (iii) a charge modulator poly-L-lysine, forming a nanoparticle matrix with a weight ratio of emulsifier to charge modulator between 4:1 and 1.5:1.
Surface charge characteristics and structure of charge modulator
The nanoparticle has a negative surface charge at neutral pH; the charge modulator is embedded in the nanoparticle matrix and extends from the surface, effectively reversing surface charge from negative to positive in acidic environments.
Improved cellular interaction and uptake
The surface modified nanoparticle exhibits greater force of adhesion to cell membranes compared to an unmodified nanoparticle lacking the charge modulator, thereby enhancing cellular uptake and intracellular delivery efficiency of therapeutic agents.
The independent claim covers the composition and structural features of a polymeric nanoparticle incorporating polyvinyl alcohol and poly-L-lysine to achieve pH-responsive charge reversal and enhanced cellular interaction. Dependent claims include the presence of therapeutic or diagnostic agents and pharmaceutical preparations thereof, as well as methods of delivering such agents using these nanoparticles.
Stated Advantages
Significantly increased cellular uptake of modified nanoparticles compared to unmodified nanoparticles.
Improved efficiency of intracellular delivery of therapeutic agents due to enhanced endosomal escape facilitated by surface charge reversal from negative to positive in acidic environments.
Greater and sustained intracellular retention of nanoparticles, enabling prolonged delivery of bioactive agents.
Surface modification provides higher affinity and force of interaction of nanoparticles with cell membranes, contributing to improved uptake.
Documented Applications
Intracellular delivery of therapeutic agents, including proteins and small molecules, using surface-modified nanoparticles.
Delivery of model proteins such as bovine serum albumin (BSA) and horseradish peroxidase (HRP) for therapeutic applications.
Potential delivery of diagnostic agents, dyes, fluorescent compounds, radio-isotopes, and contrast agents with nanoparticles.
Use in drug delivery systems targeting cellular uptake and sustained release within mammalian cells.
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