Hypoxia Responsive, Tumor Penetrating Lipid Nanoparticles for Delivery of Chemotherapeutics to Pancreatic Cancer Cell Spheroids

Abstract

Solid tumors are often poorly irrigated due to structurally compromised microcirculation. Uncontrolled multiplication of cancer cells, insufficient blood flow, and the lack of enough oxygen and nutrients lead to the development of hypoxic regions in the tumor tissues. As the partial pressure of oxygen drops below the necessary level (10 psi), the cancer cells modulate their genetic makeup to survive. Hypoxia triggers tumor progression by enhancing angiogenesis, cancer stem cell production, remodeling of the extracellular matrix, and epigenetic changes in the cancer cells. However, the hypoxic regions are usually located deep in the tumors and are usually inaccessible to the intravenously injected drug carrier or the drug. Considering the designs of the reported nanoparticles, it is likely that the drug is delivered to the peripheral tumor tissues, close to the blood vessels. In this study, we prepared lipid nanoparticles (LNs) comprising the synthesized hypoxia-responsive lipid and a peptide–lipid conjugate. We observed that the resultant LNs penetrated to the hypoxic regions of the tumors. Under low oxygen partial pressure, the hypoxia-responsive lipid undergoes reduction, destabilizing the lipid membrane, and releasing encapsulated drugs from the nanoparticles. We demonstrated the results employing spheroidal cultures of the pancreatic cancer cells BxPC-3. We observed that the peptide-decorated, drug encapsulated LNs reduced the viability of pancreatic cancer cells of the spheroids to 35% under hypoxic conditions.

Dendritic Polyglycerol‐Derived Nano‐Architectures as Delivery Platforms of Gemcitabine for Pancreatic Cancer

“…Our hypothesis was based on the fact that such programmed disintegration of larger nanoparticles will provide with deeper penetration of drug‐transporting nanocarriers through the dense desmoplastic microenvironment of pancreatic cancer. We selected pH as the stimulus to trigger such controlled destabilization because for PDAC and any other form of solid tumors, pH decreases sharply in conjunction with low O 2 tension as the distance increases from blood vessels to tumor tissues . In addition, smaller nanoparticles are required to penetrate deep‐seated tumor cells and cancer‐like stem cells, many of which are difficult to reach with larger nanoparticles due to altered microvasculature present in solid tumors.…”

Tissue‐Penetrating, Hypoxia‐Responsive Echogenic Polymersomes For Drug Delivery To Solid Tumors

“…Subsequent hydrolysis and reduction generates a shorter peptide with high affinity for the neuropilin receptors and tissue penetration capability . Nanoparticles conjugated to the iRGD peptide have been observed to penetrate into the tumors and deliver the drugs . In an in vivo study, the chemotherapeutic drugs showed better efficacy when co‐administered with the iRGD peptide .…”

“…We have used the iRGD peptide to enhance the tumor penetration of liposomes in the tumor tissues . However, polymersomes are considerably more stable compared to the liposomes, and offer better membrane stability with reduced drug release in the absence of stimulus .…”

“…[12] Nanoparticles conjugated to the iRGD peptide have been observed to penetrate into the tumors and deliver the drugs. [13,14] In an in vivo study,t he chemotherapeutic drugs showed better efficacy when co-administered with the iRGD peptide. [15] We hypothesized that iRGD functionalized, PEGylated polymersomes will penetrate deep inside tumor tissues to reacht he hypoxicr egions.…”

“…We have used the iRGD peptidetoenhancethe tumor penetration of liposomes in the tumor tissues. [13] However,p olymersomes are considerably more stable compared to the liposomes,a nd offer better membranes tabilityw ith reducedd rug releasei nt he absence of stimulus. [18] The polymer composition of the polymersomes was optimized by varying each component and determiningt he size and content release under hypoxic conditions.…”