Nanomedicine Strategies to Enhance Tumor Drug Penetration in Pancreatic Cancer

Abstract

Pancreatic cancer is one of the most malignant tumors with one of the worst survival rates due to its insidious onset and resistance to therapies. Most therapeutics show a desired anticancer effect in vitro; however, very poor efficacy in vivo because of the limited drug delivery and penetration into pancreatic tumors attributed to the abundance of the tumor stroma, ie, the fibrotic tumor microenvironment surrounding the cancer cells. For a better understanding of the challenges posed by the pancreatic tumor stroma, we outline the key features of the tumor microenvironment. Then we highlight major strategies used to tackle the challenges to improve drug penetration into the tumor and achieve enhanced efficacy (pre)clinically. Furthermore, we describe nanomedicine strategies to modulate the tumor stroma, degrade the extracellular matrix, and co-deliver multi-functional drugs, to improve the chemotherapeutics delivery and penetration into pancreatic tumors.

Recent Advances in Well-Designed Therapeutic Nanosystems for the Pancreatic Ductal Adenocarcinoma Treatment Dilemma

“…The dense tumor stroma of PDAC results in elevated interstitial fluid pressure, poor blood supply, and hypoxia in the TME. The interaction between stroma and tumor cells has a significant impact on the progression, invasion, and metastasis of PDAC [ 6 ]. Additionally, the dense fibrotic stroma severely impedes drug penetration into the PDAC tumor tissue, which leads to poor efficacy of the PDAC drug treatment.…”

“…According to a report, 496,000 cases of pancreatic cancer were diagnosed worldwide in 2020, including 466,000 deaths [ 5 ]. Pancreatic cancers are generally divided into endocrine and exocrine cancers, among which pancreatic ductal adenocarcinoma (PDAC) is an exocrine tumor, accounting for the majority (90%) of all pancreatic cancers [ 6 , 7 ]. PDAC rarely shows clinical symptoms until it develops into the advanced stage, resulting in a delay in diagnosis and treatment [ 8 ].…”

Multimodal Therapies against Pancreatic Ductal Adenocarcinoma: A Review on Synergistic Approaches toward Ultimate Nanomedicine Treatments

“…• No standard procedures [25] • Injuries to nearby systems [24] • Inadequate imaging for follow-up [413] • Intracellular hyperthermia through NPs [545][546][547] • Dynamic monitoring of PC through MRI nanoprobes [ 548] PDT • Poor penetration of photosensitizers [ 446] • Nanovehicles to better deliver photosensitizers [549][550][551][552] • Nanovehicles delivering oxygen to alleviate hypoxia [ 553,554] SDT • Limits of organic and inorganic sonosensitizers [ 451,462,555] • NPs to protect organic sonosensitizers [ 451] • Surface functionalizations of inorganic sonosensitizers [ 556] • Gas-generating nanosystems [ 557] tive accumulation, and the evidence-based importance of relying on their use by means of NP surface functionalization for efficient active targeting, [501,502] especially in stroma-rich tumors like PDAC. [503]…”

“…[571,576] These studies had the double effect of improving PDAC therapy by enhancing drug delivery into the tumor site while elucidating the complex and dual role of CAFs in desmoplasia. [577] They involved, among many other mechanisms, [503] the use of polymeric micelle-based nanoformulations to inhibit SHH pathway, [576] nab-paclitaxel to target SPARC glycoprotein, [578] miRNA inhibitors to reprogram CAFs, [579] and anti-microRNA as part of peptide-based nanocomplexes aimed at inhibiting PSC differentiation into CAFs. [580] PSCs, as stated above, are the main responsible for the increased ECM production which ultimately provokes reduced intratumoral perfusion and nanotherapeutic delivery.…”

“…[ 500 ] Taken together, these findings pointed out the role of specific ligands and tumor‐penetrating peptides in NP selective accumulation, and the evidence‐based importance of relying on their use by means of NP surface functionalization for efficient active targeting, [ 501,502 ] especially in stroma‐rich tumors like PDAC. [ 503 ]…”