Heparosan-coated liposomes for drug delivery

Abstract

Liposomal encapsulation is a useful drug delivery strategy for small molecules, especially chemotherapeutic agents such as doxorubicin. Doxil® is a doxorubicin-containing liposome ("dox-liposome") that passively targets drug to tumors while reducing side effects caused by free drug permeating and poisoning healthy tissues. Polyethylene glycol (PEG) is the hydrophilic coating of Doxil® that protects the formulation from triggering the mononuclear phagocyte system (MPS). Evading the MPS prolongs dox-liposome circulation time thus increasing drug deposition at the tumor site. However, multiple doses of Doxil® sometimes activate an anti-PEG immune response that enhances liposome clearance from circulation and causes hypersensitivity, further limiting its effectiveness against disease. These side effects constrain the utility of PEG-coated liposomes in certain populations, justifying the need for investigation into alternative coatings that could improve drug delivery for better patient quality of life and outcome. We hypothesized that heparosan (HEP; [-4-GlcA-β1-4-GlcNAc-α1-]n) may serve as a PEG alternative for coating liposomes. HEP is a natural precursor to heparin biosynthesis in mammals. Also, bacteria expressing an HEP extracellular capsule during infection escape detection and are recognized as "self," not a foreign threat. By analogy, coating drug-carrying liposomes with HEP should camouflage the delivery vehicle from the MPS, extending circulation time and potentially avoiding immune-mediated clearance. In this study, we characterize the postmodification insertion of HEP-lipids into liposomes by dynamic light scattering and coarse-grain computer modeling, test HEP-lipid immunogenicity in rats, and compare the efficacy of drug delivered by HEP-coated liposomes to PEG-coated liposomes in a human breast cancer xenograft mouse model.

Dysregulation of MicroRNAs in Hypertrophy and Ossification of Ligamentum Flavum: New Advances, Challenges, and Potential Directions

“…In addition, a variety of materials can be used as gene carriers for intracellular delivery of miRNAs (Gessler Dominic et al, 2019). For instance, liposome capsules, drug molecules with phospholipid bilayer vesicles, possess better biocompatibility and stability, which easily get into the cell through endocytosis and achieve gene delivery (Lane Rachel et al, 2017). Moreover, multiple nanosystems, such as organic/inorganic nanoparticles and polymer nanoparticles, have been introduced as functional nanocarriers to complete targeted and intelligent gene delivery by virtue of the physicochemical properties of different materials (Mao et al, 2019).…”

Enhanced cytotoxic T lymphocytes recruitment targeting tumor vasculatures by endoglin aptamer and IP-10 plasmid presenting liposome-based nanocarriers

“…These findings strongly suggest that the ENG-Apt/mIP-10-LP nanocapsules can specifically recognize tumor endothelial cell surface receptors for targeted delivery and subsequent induction of IP-10 protein expression in tumor-bearing mice. Some studies have indicated that certain size of liposome (20-200 nm) could be easier to accumulate into tumors rather than healthy tissues through the enhanced permeability and retention effect (EPR) 37, 38. In our study, the size of ENG-Apt/mIP-10-LP nanocapsules was measured 145 nm, suggesting a possible exist of EPR mechanism.…”

Ligand Binding and Signaling of HARE/Stabilin-2

“…Using homogenous synthetic heparin polymers, we have found that the heparin polymer needs to be sulfated for binding with Stabilin-1 or Stabilin-2. The nonsulfated polymer, heparosan, does not interact with the Stabilin clearance receptors and may be a good candidate as a vehicle for drug delivery [63,64]. The minimal binding requirement is for the polymer to be at least 10 sugars long and the presence of the 3- O sulfate increases binding affinity at least fivefold [53].…”