Dynamic, ultra-pH-sensitive graft copolymer micelles mediated rapid, complete destruction of 3-D tumor spheroids in vitro

Multicellular tumor spheroids: a relevant 3D model for the in vitro preclinical investigation of polymer nanomedicines

“…Liquid overlay methods. This technique mainly relies on the use of non-adherent 96-well plates, in which a coating with poly-2-hydroxyethyl methacrylate ( poly-HEMA) [52][53][54][55][56][57][58] or agarose prevents cell attachment. This method allows the preparation of both mono and hetero-type spheroids, whose size and morphology can be finely tuned by varying the number of cells seeded in each well.…”

“…37,[39][40][41]45 Optical microscopy is the simplest and most widely used technique for the visual assessment of morphological changes in spheroids. 52,[55][56][57][58][60][61][62][63][64][65]70,73,74,77,84,[89][90][91][92][93]95,107,110,[114][115][116][117][118][119][120][121][122][123][124][125][126] Following exposure to various treatments, the measurement of the variation of morphometric parameters (e.g., mean diameter, minimum diameter, maximum diameter, volume, area and circularity) of spheroids from bright field images is used for a quantitative analysis of the extent of growth inhibition. 37,87 After interruption of the treatment, the spheroid growth delay might be calculated in comparison with untreated samples as the time lag required to reach the quintuple spheroid volume of day 4 (5 × V d4 ; assuming V d4 as the starting spheroid volume at the onset of treatment).…”

“…Interestingly, size-switchable stimuli-responsive nanoparticles able to overcome multiple tumor barriers have been developed by various groups. 58,76,119,133,134,138,141 For instance, pH sensitive nanoparticles were formulated by the molecular assembly of platinum (PtIV)-prodrug conjugated polyamidoamine (PAMAM) dendrimers with two amphiphilic polymers containing either ionizable pH-responsive amide bonds (i.e., polycaprolactone-2propionic-3-methylmaleic anhydride (PCL-CDM), PCL-CDM-PAMAM/Pt nanoparticles) 134 4a). 133 Size variation as a function of pH has been evaluated on pancreatic cancer multicellular spheroids (BxPC3 cells).…”

Dynamic micelles with detachable PEGylation at tumoral extracellular pH for enhanced chemotherapy

“…Ortho esters, whose hydrolysis rate might improve 1–4 orders of magnitude compared to above acid labile linkages under mildly acidic conditions, have the potential to response to extracellular pH [20] , [21] , [22] , [23] . Moreover, our group has successfully designed a series of ultra-pH-sensitive poly(ortho ester)s-based drug delivery systems with dynamic size transitions at tumoral extracellular pH [24] , [25] , [26] , [27] . Thus, an ultra-pH-sensitive polymeric delivery system with extracellular detachable PEGylation may be constructed by optimizing the hydrophilicity of the structures surrounding the ortho ester linkages.…”

pH-sensitive, dynamic graft polymer micelles via simple synthesis for enhanced chemotherapeutic efficacy

“…For example, our group has successfully designed a series of pH-sensitive poly(ortho ester) s-based drug delivery systems with dynamic size changes at tumoral extracellular pH and rapid drug release at tumoral intracellular pH. [24][25][26] Thus, a desirable pH-sensitive and dynamic drug delivery system with simple structure and procedure for easier clinical transformation may be achieved by optimizing ortho ester (OE)-based copolymers.…”