Abstract
Nanomedicine is becoming very popular over conventional methods due to the ability to tune physico-chemical properties of nano vectors, 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 nonionic 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). In coating of niosomes, pHLIP 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.
Highlights
Most of the currently approved nano-medicinal products for cancer imaging and therapy are non-targeted nano vectors that accumulate in the tumor tissues purely through the enhanced permeability and retention (EPR) effect (Dawidczyk et al, 2014)
In both cases the major components of niosome content was Span20 and cholesterol (50 mol%) and in some niosome formulations we used fluorescent R18 (0–2 mol%). pH (Low) insertion peptide (pHLIP) was conjugated either with DSPE lipids (DSPE-pHLIP) or hydrophobic fluorescent dye, pyrene, (Pyr-pHLIP) and introduced into niosomes at amount of 5 mol%. These formulations represent two different approaches for introducing pHLIP into niosome coating: (i) pHLIP conjugated with the lipid headgroup as it was done previously (Wijesinghe et al, 2013) and (ii) pHLIP conjugated to various hydrophobic molecules, such as pyrene, which have high affinity to membrane and can intercalate into bilayer
There is an advantage of using pyrene over DSPE lipids, since (i) progression of conjugation reaction of pHLIP with pyrene is easy to monitor by HPLC and mass-spectrometry; (ii) incorporation of Pyr-pHLIP into niosomes could be assessed by measuring changes of pyrene fluorescence and (iii) pyrene could be used for intercalation into bilayers of various thicknesses
Summary
Most of the currently approved nano-medicinal products for cancer imaging and therapy are non-targeted nano vectors that accumulate in the tumor tissues purely through the enhanced permeability and retention (EPR) effect (Dawidczyk et al, 2014). Of pH (Low) insertion peptides (pHLIPVR peptides) are under development as novel agents, which target tumor acidity (Andreev et al, 2009: Weerakkody et al, 2013). The peptides sense pH at the surface of cancer cells, where it is the lowest (Anderson et al, 2016), and enters into cellular membranes (Andreev et al, 2010; Reshetnyak et al, 2006, 2007, 2008). Nanocarriers decorated with pHLIPs are biocompatible, can target tumor and demonstrate enhanced cellular uptake by cancer cells (Arachchige et al, 2015; Du et al, 2014; Wijesinghe et al, 2013; Yao et al, 2013a,2013b). In addition to pHLIP-coated nanoparticles, nanocarriers containing pH-sensitive polymers and lipids were known for decades (Chu et al, 1990; Karanth & Murthy, 2007; Lee et al, 1998; Subbarao et al, 1987)
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