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Cationic branched polymers for cellular delivery of negatively charged cargo.

ABSTRACT: Receptor-independent cellular uptake of small molecule therapeutics is limited by their physical interaction with the negatively charged surface of cellular membranes. Passive diffusion through the hydrophobic membrane bilayer follows this process. Unless specific carriers exist in the biological membrane, such interactions limit therapeutics to those that are hydrophobic with modest positive charge at physiological pH. Small negatively charged molecules are therefore not efficient as therapeutics. To enable delivery of such molecules into eukaryotic cells, cationic branched polymers with tetraalkylammonium pendant groups were synthesized by copolymerization of a functional monomer (glycidyl methacrylate) with degradable and non-degradable divinyl crosslinkers in the presence of an efficient chain transfer agent, CBr4, followed by reaction of the multiple pendant epoxide groups and most of the alkyl bromide chain ends with amines. Cationic branched polymers with covalently attached fluorescent labels entered human cancerous and non-cancerous cells. The non-labeled analogues were able to carry anionic cargo (carboxyfluorescein) into the cells, while no uptake was observed in the absence of the cationic carriers. Most of the polymers were not significantly toxic at the concentrations used. This pilot study showed that cellular uptake of anionic small molecules can be promoted even in the absence of natural uptake mechanisms.

SUBMITTER: Follit CA

PROVIDER: S-EPMC5830148 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Cationic branched polymers for cellular delivery of negatively charged cargo.

Follit Courtney A CA Woodruff Shannon R SR Vogel Pia D PD Wise John G JG Tsarevsky Nicolay V NV

Journal of drug delivery science and technology 20170407

Receptor-independent cellular uptake of small molecule therapeutics is limited by their physical interaction with the negatively charged surface of cellular membranes. Passive diffusion through the hydrophobic membrane bilayer follows this process. Unless specific carriers exist in the biological membrane, such interactions limit therapeutics to those that are hydrophobic with modest positive charge at physiological pH. Small negatively charged molecules are therefore not efficient as therapeuti ...[more]

PMID: 29503667

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Project description:Negatively charged tissues are ubiquitous in the human body and are associated with a number of common diseases yet remain an outstanding challenge for targeted drug delivery. While the anionic proteoglycans are critical for tissue structure and function, they make tissue matrix dense, conferring a high negative fixed charge density (FCD) that makes drug penetration through the tissue deep zones and drug delivery to resident cells extremely challenging. The high negative FCD of these tissues is now being utilized by taking advantage of electrostatic interactions to create positively charged multi-stage delivery methods that can sequentially penetrate through the full thickness of tissues, create a drug depot and target cells. After decades of work on attempting delivery using strong binding interactions, significant advances have recently been made using weak and reversible electrostatic interactions, a characteristic now considered essential to drug penetration and retention in negatively charged tissues. Here we discuss these advances using examples of negatively charged tissues (cartilage, meniscus, tendons and ligaments, nucleus pulposus, vitreous of eye, mucin, skin), and delve into how each of their structures, tissue matrix compositions and high negative FCDs create barriers to drug entry and explore how charge interactions are being used to overcome these barriers. We review work on tissue targeting cationic peptide and protein-based drug delivery, compare and contrast drug delivery designs, and also present examples of technologies that are entering clinical trials. We also present strategies on further enhancing drug retention within diseased tissues of lower FCD by using synergistic effects of short-range binding interactions like hydrophobic and H-bonds that stabilize long-range charge interactions. As electrostatic interactions are incorporated into design of drug delivery materials and used as a strategy to create properties that are reversible, tunable and dynamic, bio-electroceuticals are becoming an exciting new direction of research and clinical work.

Project description:Drug delivery to avascular, negatively charged tissues like cartilage remains a challenge. The constant turnover of synovial fluid results in short residence time of administered drugs in the joint space and the dense negatively charged matrix of cartilage hinders their diffusive transport. Drugs are, therefore, unable to reach their cell and matrix targets in sufficient doses, and fail to elicit relevant biological response, which has led to unsuccessful clinical trials. The high negative fixed charge density (FCD) of cartilage, however, can be used to convert cartilage from a barrier to drug entry into a depot by making drugs positively charged. Here we design cartilage penetrating and binding cationic peptide carriers (CPCs) with varying net charge, spatial distribution and hydrophobicity to deliver large-sized therapeutics and investigate their electro-diffusive transport in healthy and arthritic cartilage. We showed that CPC uptake increased with increasing net charge up to +14 but dropped as charge increased further due to stronger binding interactions that hindered CPC penetrability and uptake showing that weak-reversible binding is key to enable their penetration through full tissue thickness. Even after 90% GAG depletion, while CPC +14 uptake reduced by over 50% but still had a significantly high value of 148× showing that intra-tissue long-range charge-based binding is further stabilized by short-range H-bond and hydrophobic interactions. The work presents an approach for rational design of cationic carriers based on tissue FCD and properties of macromolecules to be delivered. These design rules can be extended to drug delivery for other avascular, negatively charged tissues. STATEMENT OF SIGNIFICANCE: Osteoarthritis (OA) remains an untreatable disease partly due to short joint residence time of drugs and a lack of delivery methods that can effectively target the dense, avascular, highly negatively charged cartilage tissue. In this study, we designed cartilage penetrating and binding cationic peptide carriers (CPCs) that, due to their optimal charge provide adequate electrical driving force to rapidly transport OA drugs into cartilage and reach their cell and matrix targets in therapeutic doses before drugs exit the joint space. This way cartilage is converted from being a barrier to drug entry into a drug depot that can provide sustained drug release for several weeks. This study also investigates synergistic effects of short-range H-bond and hydrophobic interactions in combination with long-range electrostatic interactions on intra-cartilage solute transport. The work provides rules for rational design of cartilage penetrating charge-based carriers depending on the net charge of tissue (normal versus arthritic), macromolecule to be delivered and whether the application is in drug delivery or tissue imaging.

Dataset Information

Cationic branched polymers for cellular delivery of negatively charged cargo.

Publications

Cationic branched polymers for cellular delivery of negatively charged cargo.

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