Multilayer Hydrogel Capsules of Interpenetrated Network for Encapsulation of Small Molecules

Abstract

We report on a facile capsule-based platform for efficient encapsulation of a broad spectrum of hydrophilic compounds with molecular weight less than 1000 g mol. The encapsulated compounds extend from low-molecular-weight anionic Alexa Fluor 532 dye and cationic anticancer drug doxorubicin (DOX) to fluorescein isothiocyanate-dextrans with M ranging from 4000 to 40 000 g mol. The pH-sensitive hydrogel capsules with an interpenetrated network shell are synthesized by layer-by-layer assembly of poly(methacrylic acid) (PMAA, M = 150 000 g mol) and poly( N-vinylpyrrolidone) (PVPON, M = 1 300 000 g mol) on 5 μm silica microparticles followed by chemical cross-linking of the PMAA multilayers. Following core dissolution, the result is a hollow microcapsule with PVPON interpenetrated in the PMAA network. The capsules exhibit a reversible change in the diameter with a swelling ratio of 1.5 upon pH variation from 7.5 to 5.5. Capsules cross-linked for 4 h display high permeability toward molecules with molecular weight under 1000 g mol at pH = 7.5 but exclude dextran molecules with M ≥ 40 000 g mol. Encapsulation of small molecules was achieved at pH = 7.5 followed by sealing the capsule wall with 40 000 g mol dextran at pH = 5.5. This approach results in negatively charged molecules such as Alexa Fluor being entrapped within the capsule cavity, whereas positively charged molecules such as DOX are encapsulated within the negatively charged capsule shell. Considering the simple postloading approach, the ability to entrap both anionic and cationic small molecules, and the pH-responsiveness of the interpenetrated network in the physiologically relevant range, these capsules offer a versatile method for controlled delivery of multiple hydrophilic compounds.

Encapsulation and Ultrasound-Triggered Release of G-Quadruplex DNA in Multilayer Hydrogel Microcapsules

“…As reported previously, the cystamine-crosslinked PMAA network demonstrated pH-dependent swelling at pH > 6 and pH < 5 because of ionization of carboxylic and amine groups, respectively, similar to that observed for PMAA multilayer hydrogels cross-linked with ethylenediamine [34,63]. However, we have shown earlier that the entrapment of PVPON within the capsule wall as well as a high crosslink density can drastically change the pH-swelling profile of (PMAA/PVPON) hydrogels [71]. Thus, the presence of long PVPON chains highly entangled within the PMAA capsule hydrogel shell was shown to suppress mobility of PMAA segments between the crosslinks.…”

“…Specifically, when the molecular weight of PVPON in PMAA/PVPON hydrogen-bonded multilayer template films was increased to 1,300,000 Da (1300 kDa), only 18% of the PVPON content was released due to the increased chain entanglement in comparison to shorter (58 kDa) PVPON polymer chains [76]. In another recent study, we have demonstrated that hydrogel capsules made of interpenetrated (PMAA/PVPON) multilayers can be obtained by dipped multilayer assembly of PMAA ( M w = 150,000 Da) and PVPON ( M w = 1,300,000 Da) on porous and solid silica microparticles followed by chemical crosslinking of PMAA [71]. Because of its high molecular weight, PVPON was physically entrapped within the PMAA network and did not diffuse out from the network at pH = 8 [71].…”

“…In another recent study, we have demonstrated that hydrogel capsules made of interpenetrated (PMAA/PVPON) multilayers can be obtained by dipped multilayer assembly of PMAA ( M w = 150,000 Da) and PVPON ( M w = 1,300,000 Da) on porous and solid silica microparticles followed by chemical crosslinking of PMAA [71]. Because of its high molecular weight, PVPON was physically entrapped within the PMAA network and did not diffuse out from the network at pH = 8 [71]. In our current work, we utilized high molecular weight PMAA (100 kDa) and PVPON (1300 kDa) to create capsules of (PMAA/PVPON) n interpenetrated multilayer hydrogel using sacrificial porous calcium carbonate particles with the aim of increasing the retention of loaded DNA molecules.…”

“…In addition to the type of stimulus applied to microcapsule drug carriers, an important parameter controlling the encapsulation and release of therapeutic cargo is the pore size of the shell network. Regarding this, we have shown that hollow microcapsules with shells made of interpenetrated networks of PMAA/PVPON are capable of efficiently loading and releasing hydrophilic model therapeutics from among a wide range of molecular weights [71]. While we demonstrated the use of this new system for low molecular weight ( M w < 1000 Da) small molecules, we now show that the microcapsules with interpenetrated PMAA/PVPON shell networks allow efficient loading and precisely controlled release of nucleic acid oligomers and longer double stranded sequences.…”

Destruction of Polyelectrolyte Microcapsules Formed on CaCO3 Microparticles and the Release of a Protein Included by the Adsorption Method

“…There are several articles describing the release of low molecular weight drugs from polysaccharide microcapsules. Thus, it was shown in [16][17][18][19] that multilayer microcapsules, whose shell has different thickness and composition, provide effective prolonged release of water-soluble drugs such as furosemide, ibuprofen and dexamethasone. In addition, the literature describes the yield of high molecular weight substances.…”