Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth cause of cancer-related mortality in the Western world and is envisaged to become the second cause by 2030. Although our knowledge about the molecular biology of PDAC is continuously increasing, this progress has not been translated into better patients’ outcome. Liposomes have been used to circumvent concerns associated with the low efficiency of anticancer drugs such as severe side effects and damage of healthy tissues, but they have not resulted in improved efficacy as yet. Recently, the concept is emerging that the limited success of liposomal drugs in clinical practice is due to our poor knowledge of the nano–bio interactions experienced by liposomes in vivo. After systemic administration, lipid vesicles are covered by plasma proteins forming a biomolecular coating, referred to as the protein corona (PC). Recent studies have clarified that just a minor fraction of the hundreds of bound plasma proteins, referred to as “PC fingerprints” (PCFs), enhance liposome association with cancer cells, triggering efficient particle internalization. In this study, we synthesized a library of 10 liposomal formulations with systematic changes in lipid composition and exposed them to human plasma (HP). Size, zeta-potential, and corona composition of the resulting liposome–protein complexes were thoroughly characterized by dynamic light scattering (DLS), micro-electrophoresis, and nano-liquid chromatography tandem mass spectrometry (nano-LC MS/MS). According to the recent literature, enrichment in PCFs was used to predict the targeting ability of synthesized liposomal formulations. Here we show that the predicted targeting capability of liposome–protein complexes clearly correlate with cellular uptake in pancreatic adenocarcinoma (PANC-1) and insulinoma (INS-1) cells as quantified by flow-assisted cell sorting (FACS). Of note, cellular uptake of the liposomal formulation with the highest abundance of PCFs was much larger than that of Onivyde®, an Irinotecan liposomal drug approved by the Food and Drug Administration in 2015 for the treatment of metastatic PDAC. Given the urgent need of efficient nanocarriers for the treatment of PDAC, we envision that our results will pave the way for the development of more efficient PC-based targeted nanomaterials. Here we also show that some BCs are enriched with plasma proteins that are associated with the onset and progression of PDAC (e.g., sex hormone-binding globulin, Ficolin-3, plasma protease C1 inhibitor, etc.). This could open the intriguing possibility to identify novel biomarkers.
Highlights
With a one-year survival rate of 12% that declines to 1% at five years, pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal tumors worldwide [1]
We show that the predicted targeting capability of liposome–protein complexes clearly correlate with cellular uptake in pancreatic adenocarcinoma (PANC-1) and insulinoma (INS-1) cells as quantified by flow-assisted cell sorting (FACS)
Cellular uptake of the liposomal formulation with the highest abundance of PC fingerprints” (PCFs) was much larger than that of Onivyde®, an Irinotecan liposomal drug approved by the Food and Drug Administration in 2015 for the treatment of metastatic Pancreatic ductal adenocarcinoma (PDAC)
Summary
With a one-year survival rate of 12% that declines to 1% at five years, pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal tumors worldwide [1]. As a consequence of PC formation, liposomes lose their synthetic identity and attain a new one that is usually referred to as their “biological identity” It is this newly acquired biological identity that controls undesirable side effects of liposomal drug delivery, such as off-target interactions, toxicity, size-dependent particle recognition by immune cells [27], and clearance from the bloodstream [28,29]. In a couple of recent investigations [26,30], we demonstrated that liposomes possessing specific size and zeta-potential are efficiently internalized within cancer cells [26,30]. A minor fraction of identified “corona proteins” (typically 1–2%), referred to as “protein cceolrlounlaar fainssgoecripartiinotns.”G(lPoCbFasll)y,, plirpoomsoomteefapvhoyrsaibcalel-ccheellmuliacralapssroocpiearttioiens., PGClocboamllyp,olsipitoiosno,maendphceylsliuclaalruchpetamkiecaclanprboepceortmiebsi,nPeCd icnoma gpeonseitriaolns,tarantdegcyeltloulparreudpicttatkheecinanterbaectcioomn boifnleipdoisnoma egsenweirtahlcsatnracteergcyeltlos (pFriegduircet 1th).e interaction of liposomes with cancer cells (Figure 1)
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