pH-sensitive pHLIP^® coated niosomes

Abstract

Nanomedicine is becoming very popular over conventional methods due to the ability to tune physico-chemical properties of nanovectors, which are used for encapsulation of therapeutic and diagnostic agents. However, the success of nanomedicine primarily relies on how specifically and efficiently nanocarriers can target pathological sites to minimize undesirable side effects and enhance therapeutic efficacy. Here, we introduce a novel class of targeted nano drug delivery system, which can be used as an effective nano-theranostic for cancer. We formulated pH-sensitive niosomes (80–90 nm in diameter) using non-ionic surfactants Span20 (43–45 mol%), cholesterol (50 mol%) and 5 mol% of pH (Low) Insertion Peptide (pHLIP) conjugated with DSPE lipids (DSPE-pHLIP) or hydrophobic fluorescent dye, pyrene, (Pyr-pHLIP). pHLIP in coating of niosomes was used as an acidity sensitive targeting moiety. We have demonstrated that pHLIP coated niosomes sense the extracellular acidity of cancerous cells. Intravenous injection of fluorescently labeled (R18) pHLIP-coated niosomes into mice bearing tumors showed significant accumulation in tumors with minimal targeting of kidney, liver and muscles. Tumor-targeting niosomes coated with pHLIP exhibited 2–3 times higher tumor uptake compared to the non-targeted niosomes coated with PEG polymer. Long circulation time and uniform bio-distribution throughout the entire tumor make pHLIP-coated niosomes to be an attractive novel delivery system.

Galactose-Modified PH-Sensitive Niosomes for Controlled Release and Hepatocellular Carcinoma Target Delivery of Tanshinone IIA

“…CHEMS self-assemble into a bimolecular layer in alkaline and neutral aqueous media and therefore fuse with the bimolecular layer of niosomes, whereas they rupture the bimolecular layer in acidic media to facilitating drug release ( 21 ). Intracellular and extracellular acidity has been recognized as a common feature of tumor tissue ( 22 , 23 ), and the intracellular acidity is the stronger characteristic ( 24 – 26 ). When niosomes containing CHEMS encounter tumor cells, the bimolecular layer becomes unstable due to the environmental acidity, thus promoting release of the payload ( 27 ).…”

Decoration of Nanovesicles with pH (Low) Insertion Peptide (pHLIP) for Targeted Delivery

“…pHLIP was conjugated with DSPE lipids in methanol by the covalent conjugation of DSPE-maleimide with the single cysteine residue at the N-terminus of pHLIP, as it was described previously [18, 21, 22]. Briefly, 5 mg of peptide dissolved in 250 μL methanol (blown with argon) and DSPE-maleimide (from 9.9 mM stock solution) dissolved in chloroform were mixed at a molar ratio of 1:1.…”

“…Nanocarriers decorated with pHLIPs are biocompatible, can target tumors, and demonstrate enhanced cellular uptake by cancer cells. Among investigated pHLIP-coated nanoparticles are lipid, polymer, and metal-based nanomaterials [18–21].…”

Recent Progress of Nanocarrier-Based Therapy for Solid Malignancies

“…At the same time, niosomes have lower manufacturing costs and longer shelf life, and their bilayer fluidity and microviscosity could be easily regulated. pH (Low) insertion peptide (pHLIP)-coated niosomes were successfully developed by Pereira et al [ 41 ]. Compared with pHLIP-coated liposomes, pHLIP-coated niosomes are smaller and more stable, with pH-dependent cell uptake and excellent tumor targeting.…”