Spermine modified polymeric micelles with pH-sensitive drug release for targeted and enhanced antitumor therapy

Abstract

Tumor targeting delivery of chemotherapeutic drugs by nanocarriers has been demonstrated to be a promising strategy for cancer therapy with improved therapeutic efficacy. In this work, we reported a novel type of active targeting micelle with pH-responsive drug release by using biodegradable poly(lactide)-poly(2-ethyl-2-oxazoline) di-block copolymers functionalized with spermine (SPM). SPM has been considered as a tumor binding ligand through its specific interaction with the polyamine transport system (PTS), a transmembrane protein overexpressed on various types of cancer cell, while its application in nano-drug delivery systems has rarely been explored. The micelles with spherical shape ($110 nm) could load hydrophobic paclitaxel (PTX) with high capacity, and release the payload much faster at acidic pH (4.5-6.5) than at pH 7.4. This pH-responsive property assisted the rapid escape of drug from the endo/lysosome after internalization as demonstrated by confocal laser scanning microscopy images using coumarin-6 (Cou-6) as a fluorescent probe. With surface SPM modification, the micelles displayed much higher cellular uptake than SPM lacking micelles in various types of cancer cells, demonstrating tumor targeting ability. The uptake mechanism of SPM modified micelles was explored by flow cytometry, which suggested an energy-consuming sag vesicle-mediated endocytosis pathway. As expected, the micelles displayed significantly enhanced anti-cancer activity. This work demonstrates that SPM modified pH-sensitive micelles may be potential drug delivery vehicles for targeting and effective cancer therapy.Scheme 1 Tumor targeting delivery of SPM functionalized micelles via PTS binding and their endocytosis and pH-triggered endo/lysosome drug release for anti-cancer therapy.This journal is

Platensimycin-Encapsulated Liposomes or Micelles as Biosafe Nanoantibiotics Exhibited Strong Antibacterial Activities against Methicillin-Resistant Staphylococcus aureus Infection in Mice

“…PEOz is approved by the US Food and Drug Administration as a food additive. In recent years, PEOz is widely used in pH-responsive drug targeted delivery systems as the substituent of PEG, because it can promote the rapid release of drug in acidic phagolysosomes. −, However, since there is only a small difference of the in vitro release behavior of PLGA–PEOz/PTM in pH 7.4 and 5.5 (Figure C), the potential electrostatic interactions between PTM and PLGA–PEOz might only be a minor factor for the release of PTM from PLGA–PEOz/PTM nanoparticles. ,, We next studied the pH-responsive drug release properties of PLGA–PEOz/PTM (Figure C). There was no significant difference in the cumulative release of nonsensitive PLGA–PEG/PTM at pH 7.4 and 5.5, respectively, while the release of PTM from PLGA–PEOz/PTM increased at pH 5.5.…”

Naturally Equipped Urinary Exosomes Coated Poly (2−ethyl−2−oxazoline)−Poly (D, L−lactide) Nanocarriers for the Pre−Clinical Translation of Breast Cancer

“…Thereafter, the resulting stripped film was hydrated using 5 mL of deionized water at 60 °C and the mixture was further vortexed for 5 min. The unloaded DOX was removed by filtering the NPs suspension through a 0.22 μm pore size membrane [ 25 , 26 , 28 ]. For synthesis of DiR−loaded NPs (PP−DiR NPs), 20 mg PEOz−PLA and 1 mg DiR (pre−dissolved in 10% DMSO) were dissolved in methanol (20 mL).…”

“…Moreover, UEs from breast cancer patients present similar membrane antigens to cancer cell, such as E−cadherin and CD 47, thereby providing “Trojan horses” for specific drug delivery to tumor site. Most importantly, UEs from breast cancer patients carry more abundant key proteins (CD63, CD9, and CD47) as compared to that from normal people, which are essential for long blood circulation, immune escape and tumor targeting [ 1 , 23 , 26 ]. In view of the above, we believe that UE−based biomimetic nanoparticles could provide a new nanoplatform for individualized therapy.…”

Thioacetate‐Based Initiators for the Synthesis of Thiol‐End‐Functionalized Poly(2‐oxazoline)s

“…This method has been rather parsimoniously used in the synthesis of α‐functional PAOx. Example of protecting groups incorporated in cROP initiators include N ‐alkylphthalimide or tert ‐butyl N ‐monoalkylcarbamate (for amines), [ 52–56 ] tert‐ butyldiphenylsilyl ethers (for hydroxyl), [ 57 ] methyl ester (for carboxylic acid or others through amidation), [ 58–63 ] and furanyl Diels–Alder cycloadduct (for maleimide). [ 64 ] Here, the thioacetate group has been chosen as a stable and economic protection group for thiols.…”