Jing-Bo Yang,De-Zhong Xu,Zi-Han Zhang,Xi Zhang,Zhi-Xuan Ren,Zhong-Lin Lu,Rui Liu,Yang Liu
Maximizing drug cargo carrying capacity in blood circulation, controlling the in vivo fate of nanoparticles, and precisely drug release to tumor targets are the main aims of multifunctional nanomedicine-based antitumor therapy. Here we combined macrocyclic polyamine di(triazole-[12]aneN3) (M) and chemical drug camptothecin (CPT, C) through photosensitizer 1,1-dicyano-2-phenyl-2-(4-diphenylamino) phenyl-ethylene (DT) containing the cleavable disulfide (S) linkage as an all-in-one theranostic nanoprodrug, MDTSC. The corresponding compound with carbon chain (C) linkage, MDTCC, was also prepared for a comparison study. MDTSC showed the ability to carry plasmids, including the p53 tumor suppressor gene, to form lipoplexes with a size of ∼150 nm. Further addition of DOPE-PEG2k resulted in the hybrid lipoplexes MDTSC/DOPE-PEG2k@DNA, which showed good stability in blood circulation and good biocompatibility to normal cell lines. Experiments demonstrated that the hybrid lipoplexes were able to realize the successful cellular uptake and endosomal escape, to generate ROS under visible light irradiation as well as to trigger the localized release of CPT and the plasmid encoding p53 in tumor cells. In vitro, the hybrid lipoplexes showed better EGFP expression than the commercial Lipo2000, and markedly reduced tumor cell proliferation and migration rate irrespective of whether the BxPC-3 cell lines were grown on plates or 3D tumor spheroids. In vivo, the hybrid lipoplexes showed effective anticancer activity by reducing the BxPC-3 pancreatic tumor growth by 99% through the synergetic combination of chemotherapy, photodynamic therapy, and gene therapy. This research represented the first example of using a cocktail of three therapeutic approaches to achieve cooperative and effective anti pancreatic cancer treatment in vivo and in vitro.
Haijie Han,Jinhui Wang,Tingting Chen,Lichen Yin,Qiao Jin,Jian Ji
Development of gemcitabine (GEM) nanocarriers as theranostic agents for pancreatic cancer chemotherapy has received extensive attention in recent years. A novel enzyme-sensitive albumin-based GEM delivery nanoplatform was developed in this research by simple conjugation of GEM to human serum albumin (HSA) via cathepsin B cleavable peptide GFLG and then complexing with near-infrared (NIR) dye IR780, forming a HSA-GEM/IR780 complex. The successful preparation of HSA-GEM/IR780 complex was confirmed by Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOF-MS), UV–vis–NIR absorption spectra and fluorescent emission spectra . The in vivo performance of HSA-GEM/IR780 complex was carried out on BxPC-3 pancreatic tumor xenografted mice. As revealed by in vivo NIR imaging, HSA-GEM/IR780 exhibited enhanced accumulation and long-term retention in tumor tissues compared to free IR780. Meanwhile, compared to free GEM, the deamination of GEM nanovectors into inactive 2′,2′-difluorodeoxyuridine (dFdU) can be greatly suppressed, while the concentration of the activated form of GEM (gemcitabine triphosphate, dFdCTP) was significantly increased in tumor tissue, thus exhibiting superior tumor inhibition activity with minimal side effects.
Pancreatic tumor is extremely lethal because its cancerous structures are sheltered by dense stromal barriers that hinder the infiltration of therapeutics. To facilitate the infiltration of therapeutics through the stromal barrier, remodeling the stroma with an adjuvant prior to or together with gemcitabine—the current chemotherapeutic standard for pancreatic cancer—is a widely studied strategy; nevertheless, the intrinsic nonuniformity in distribution (spatial and/or temporal) of the adjuvant and gemcitabine has raised the increased risk of tumor metastasis as a major concern. In this work, we propose long-circulating, pH-sensitive nanoparticles composed solely of cellular membrane-disruptive molecules as a new approach for treating pancreatic cancer. Using a micelle of a polymeric mimetic of host defense peptides as the model for such nanoparticles, we showed that this nanoparticle exhibited acid-activated cytotoxicity indiscriminately to both cancerous and fibroblast cells, and the underlying activity mode was acid-activatable disruption of cellular membrane integrity. As a result, our acid-activatable nanoparticle effectively permeabilized the stromal barrier and eradicated the otherwise sheltered pancreatic cancer cells, as demonstrated with a three-dimensional spheroid in which a shell of fibroblast NIH-3T3 cells was cultured over a core of pancreatic BxPC-3 cells. When administered intravenously into mouse models bearing xenograft pancreatic BxPC-3 tumors, our acid-activatable nanoparticle efficiently inhibited tumor growth without causing noticeable off-target adverse effects or promoting tumor metastasis. Notably, this nanoparticle permeabilized the otherwise dense pancreatic tumor tissue while significantly suppressing the expression of extracellular matrix components and activated cancer-associated fibroblasts. Although the feasibility of our approach was demonstrated with a micelle of a polymeric molecule, we trust that future research efforts in this pathway may eventually offer translational formulations for improving the therapeutic efficacy of pancreatic cancer.
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