Transcytosis Mediated Deep Tumor Penetration for Enhanced Chemotherapy and Immune Activation of Pancreatic Cancer

Abstract

The hyperproliferative tumor stroma of pancreatic ductal adenocarcinoma (PDAC) severely limits drug permeation and constructs an immunosuppressive microenvironment, causing resistance to chemotherapy and immunotherapy. Traditional nanomedicine mainly focuses on manipulating nanoparticles’ particle size or electrical characteristics to penetrate deep PDAC through the paracellular pathway, but the transcellular pathway is often ignored. Therefore, a versatile drug‐polymer conjugate PODEA‐Gem‐HMI is prepared and assembled into nanoparticles for the codelivery of chemotherapy drug gemcitabine and focal adhesion kinase (FAK) inhibitor defactinib. While sensing the mild acidity in the tumor microenvironment, the nanoparticle will disintegrate and release defactinib to modulate the tumor stroma. The PODEA block of the conjugate can bind with cell membranes reversibly and trigger adsorption‐mediated transcytosis (AMT) for promoted tumor penetration and cellular uptake. The internalized conjugates will release gemcitabine responding to the overexpressed glutathione (GSH) for enhanced chemotherapy, and PHMI can condensate the STING monomers for prolonged spontaneous immune stimulation.

Enhancing drug penetration in solid tumors via nanomedicine: Evaluation models, strategies and perspectives

“…Absorptive-mediated transcytosis (AMT), a specific type of transcytosis, is executed by recruiting nanomedicine onto a cell surface, triggering cellular internalization and transcellular transport [ 238 ]. This process is particularly attracting because nanocarriers in nanomedicine can penetrate multiple cell layers in tumor tissues [ 239 , 240 ]. To ensure safety and efficacy of nanomedicine and promote tumor penetration through AMT, a sufficiently high cellular uptake efficiency is critical for AMT.…”

Breaking Down Barriers in Drug Delivery by Stromal Remodeling Approaches in Pancreatic Cancer

“…Yu et al conjugated this fragment to multifunctional nanoparticles loaded with FAK inhibitor, Sting activator, and chemotherapy drug, and delivered the multifunctional nanoparticles deep into the tumor, realizing the combination of stroma remodeling with immunotherapy and chemotherapy. 122 Among them, the FAK inhibitor improved the dense stroma of pancreatic cancer and further promoted the accumulation of multifunctional nanoparticles in the tumor. And Sting activator promoted dendritic cell maturation and CD8 + T cell infiltration to achieve effective immunotherapy.…”

“…Poly­(2-(N-oxide-N, N-diethylamino)­ethyl methacrylate) (PODEA) is a zwitterionic polymer that shows a high affinity for the cell membrane and can trigger the endocytic mechanism. Yu et al conjugated this fragment to multifunctional nanoparticles loaded with FAK inhibitor, Sting activator, and chemotherapy drug, and delivered the multifunctional nanoparticles deep into the tumor, realizing the combination of stroma remodeling with immunotherapy and chemotherapy . Among them, the FAK inhibitor improved the dense stroma of pancreatic cancer and further promoted the accumulation of multifunctional nanoparticles in the tumor.…”

Achieving deep intratumoral penetration and multimodal combined therapy for tumor through algal photosynthesis

“…Alternatively, structural alterations of the carrier can be implemented to transition from larger to smaller morphologies, thereby enhancing intratumoral penetration efficiency [ 4 , 5 ]. Additionally, utilizing endocytosis facilitates carrier transmission between tumor cells, enabling deep-seated delivery of the carrier to the tumor [ 6 , 7 ]. In our earlier investigations, our team observed that apart from the inherent properties of the carrier, the significantly elevated interstitial fluid pressure at the tumor site greatly hinders the efficiency of drug delivery.…”