pH-sensitive pHLIP^® coated niosomes

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.

Keywords:

• Drug delivery
• targeting tumor acidity
• fluorescence imaging

Acknowledgments

We would like to thank Dr. Al Bach and Kim Andrews, Rhode Island IDeA Network for Excellence in Biomedical Research (INBRE), for their assistance in using the cello meter; Dr. Richard Kingsley and Dr. Iftheker Khan, University of Rhode Island, for performing TEM imaging; Mr Paul W Johnson, RI Genomic and Sequencing Center for his assistance in confocal microscopy, Dr. Dammika Weerakkody, University of Rhode Island for his assistance on biophysical instrumentation and Mr. Troy Crawford, University of Rhode Island for his assistance in animal studies.

Disclosure statement

OA Andreev and YK Reshetnyak have founded and have a financial interest in a company, pHLIP, Inc., with the aim of bringing pHLIP technology to the clinic. The company has had no involvement in funding the studies reported here.

Additional information

Funding

This work was supported by the National Institutes of General Medical Sciences grant R01GM073857 to OAA and YKR. Also, this research was supported in part by an Institutional Development Award (IDeA) Network for Biomedical Research Excellence from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20GM103430.