In contrast, 2 m IPLVVPL-PMAA hydrogels had suppressed cell internalization compared to the peptide-free PMAA hydrogels. internalization by malignancy cells. The cell uptake kinetics and the ultimate extent of internalization is usually controlled by the cell type and hydrogel size. The peptide modification significantly promotes the uptake of the 700 nm hydrogels by hepsin-positive MCF-7 cells due to ligand-receptor acknowledgement but has a negligible effect on the uptake of 2-m PMAA hydrogels. The selectivity of 700-nm IPLVVPL-PMAA hydrogel cubes to hepsin-overexpressing tumor cells is usually further confirmed by Phosphoramidon Disodium Salt a 3- to 10-fold higher particle internalization by hepsin-positive MCF-7 and SK-OV-3 compared to hepsin-negative PC-3 cells. This work provides a facile method to fabricate enhanced tumor-targeting service providers of submicrometer size and enhances the general understanding of particle design parameters for targeted drug delivery. blood circulation, and biodistribution13,14 In this respect, studies on targeting efficacy have been mostly focused on nano-systems (< 500 nm) due to the ease of particle synthesis, favorable cellular uptake, and localization in tumor tissue due to the enhanced permeability and retention (EPR) effect.14,15 For instance, 50-nm mesoporous silica particles were reported to have the largest internalization by Hela cells among a series of particles in the 30C280 nm size range.16 Similarly, although drug-loaded micelles ranging from 30 to 100 nm in size showed accumulation in tumor sites, the 30-nm micelles demonstrated extraordinary penetration even into poorly permeable tumors. 17 In contrast to the particles discussed above, other biologically active entities both natural and synthetic exhibit a wide size distribution over nm to m scales.18,19 For example, despite their slightly larger size, the EPR SH3RF1 effect was observed for bacteria larger than 1 m.20 Micron-sized red blood cells have also been exhibited as effective bioactive vehicles for targeted drug delivery.21,22 Synthetic soft PRINT (Particle Phosphoramidon Disodium Salt Replication in Nonwetting Themes) hydrogels ranging from 0.8 to 8.9 m exhibited longer circulation time when their size approached that of red blood cells, further demonstrating the potential of micron-sized particles Phosphoramidon Disodium Salt for drug delivery.23 Increasing the size of hydrogel rods from 400 to 800 nm also improved their cellular uptake.24 The above observations have inspired the development of Phosphoramidon Disodium Salt soft synthetic carriers of sub-micrometer (>500 nm) to micrometer size (1C5 m) for tumor detection and/or therapy. Importantly, the ability to tune the particle rigidity/elasticity Phosphoramidon Disodium Salt is among the main advantages of polymeric vehicles as drug service providers as it allows for a facile regulation of their biological activity.25 Thus, decreasing the elastic modulus of polyethylene glycol (PEG) nanogels from 3000 to 10 kPa was shown to increase their circulation up to 2 hours.26 Prolonged circulation in blood was also observed for micron-sized PRINT hydrogels where the 8-fold lower elastic moduli of the particles led to a 30-fold increase in the elimination half-life.27 In addition to affecting the blood circulation time, tuning the elasticity of particles can regulate their association with malignancy cells and improve the accumulation in targeted sites.26 A recent study has demonstrated that softer nanoliposomes (45kPa) are 2.6-fold more efficient in accumulating in 4T1 tumors compared to harder particles (19 MPa), indicating the advantages of reduced elasticity for the tumor targeting ability of particles.28 While those fundamental associations have been elucidated, research on the effect of particle size (from supra-nano to submicron and micron size) in conjunction with relevant variables such as polymer chemistry, surface modification, and cell type around the targeting ability of the carrier is still in its infancy, possibly due to the challenge of simultaneously fine tuning all these parameters. In this regard, template-assisted layer-by-layer (LbL) assembly is usually a powerful approach to meet the requirements regarding particle synthesis.29,30,31 This method relies on the sequential adsorption of macromolecules on a sacrificial particulate template, which affords precise control over particle size, shape, and composition, as well as physical and biological properties.32C 33, 34, 35, 36 Submicron- or micrometer-sized multilayer capsules were successfully internalized by varies cell types.29,37,38,39 The internalization of m-sized capsules could be attributed to their elasticity and flexibility which allow for deformation and shape change during the cell uptake course of action.38 For example, 3-m (tannic aicid/poly(N-vinylpyrrolidone)) (TA/PVPON) capsules can pass through 0.8-m pores, demonstrating their possible extravasation which can be utilized for passive targeting of tumors.38 Multilayer microcapsules have also been shown useful for various applications.40,41 We have recently developed porous poly(methacrylic acid) (PMAA) multilayer-derived hydrogels of cubical and spherical designs with pH- and redox-sensitivity which are capable of encapsulation and stimuli-triggered release of hydrophilic doxorubicin and hydrophobic 7-(benzylamino)-3,4-dihydro-pyrrolo[4,3,2-de]quinolin-8(1H)-one (BA-TPQ) anticancer drugs. 42,43,44 Those particles were obtained upon cross-linking of PMAA in PMAA/poly(vinylpyrrolidone) (PVPON) multilayers put together within mesoporous sacrificial themes. As compared to hollow capsules, these network particles provide much larger surface area due to the polymer network distributed throughout the entire particle volume, which is usually important for drug loading efficiency and release. 42 In this work, we report on a facile.
