Zhijie Liang,Jinzhuai Li,Hai Huang,Hongmian Jiang,Lifeng Luo,Shaorong Li,Huali Huang,Fangdi Hu
Pancreatic ductal adenocarcinoma (PDAC) poses significant therapeutic challenges due to its unique tumor microenvironment, which is characterized by collapsed blood vessels and elevated intratumoral pressure, severely hindering drug penetration and distribution. Consequently, we synthesized glucose-modified PEG-PLA (polyethylene-polylactice acid) nanoparticles as a drug delivery system for doxorubicin (DOX). We successfully enhanced the permeability and targeting capability of the nanoparticles in pancreatic cancer cells using glycosylation modification, significantly increasing drug accumulation within the tumor microenvironment. Our study demonstrated excellent cellular uptake of the nanoparticles in vitro and their improved penetration in 3D tumor spheroid models. Additionally, in vivo experiments revealed a notable increase in nanoparticle accumulation at the tumor site, along with favorable drug release characteristics. Hence, glucose-modified PEG-PLA nanoparticles hold substantial potential for clinical application in PDAC treatment, effectively enhancing the therapeutic efficacy of chemotherapeutic agents.
Shi Yanan,Zhu Haibo,Ren Yan,Li Keke,Tian Baocheng,Han Jingtian,Feng Dongxiao
Poly(ethylene glycol)-poly(D,L-lactide) (PEG-PLA), a type of copolymer widely used for drug delivery, was synthesized in the present work based on previous studies, which is used for bovine serum albumin (BSA)-loaded micelle formulation. The micelles exhibited less than 100 nm in size with narrow polydispersity indices (PDI) of smaller than 0.3, and showed an encapsulation efficiency of 69%. BSA was encapsulated in the PEG-PLA micelle successfully exhibiting intact structure indicated by native polyacrylamide gel electrophoresis (Native-PAGE), fluorescence spectroscopy and fourier transform infrared spectroscopy (FTIR) analysis methods. It investigated the effects of freeze-drying, varying amount of cryoprotectants (sucrose, mannitol and lactose), and ultrasonication treatment on the size, and size distribution. The micelles were agglomerated in the freeze-drying process demonstrated by transmission electron microscope (TEM) and dynamic light scattering (DLS) analysis. Five percent of mannitol and ultrasonication for 90 s were found producing a significant reduction in agglomeration as well as a sharp decrease in size. The results demonstrated suitable cryoprotectant, and ultrasonication are beneficial to control the size and distribution of protein-loaded PEG-PLA micelle.
The combination of photodynamic therapy (PDT) and chemotherapy holds great potential in combating drug-resistant cancers. However, the major challenge that lies ahead is how to achieve high coloading capacity for both photosensitizer and chemo-drugs and how to gain efficient delivery of drugs to the drug-resistant tumors. In this study, we prepared a nanovehicle for codelivery of photosensitizer (pyropheophorbide-a, PPa) and chemo-drugs (paclitaxel, PTX) based on the synthesis of PPa-conjugated amphiphilic copolymer PPa-PLA-PEG-PLA-PPa. The obtained nanoparticles (PP NP) exhibited a satisfactory high drug-loading capacity for both drugs. To achieve effective tumor-targeting therapy, the surface of PP NP was decorated with a tumor-homing and penetrating peptide F3. In vitro cellular experiments showed that F3-functionalized PP NP (F3-PP NP) exhibited higher cellular association than PP NP and resulted in the strongest antiproliferation effect. In addition, compared with the unmodified nanoparticles, F3-PP NP exhibited a more preferential enrichment at the tumor site. Pharmacodynamics evaluation in vivo demonstrated that a longer survival time was achieved by the tumor-bearing mice treated with PP NP (+laser) than those treated with chemotherapy only or PDT only. Such antitumor efficacy of combination therapy was further improved following the F3 peptide functionalization. Collectively, these results suggested that targeted combination therapy may pave a promising way for the therapy of drug-resistant tumor.
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