Block copolymer micelles find application in many fields as nanocarriers, especially in drug delivery. We report herein that specific interactions between hydrophobic guest molecules and core-forming segments can significantly improve the loading capacity of polymeric micelles. High loading capacities (>100% weight/weight of polymer (w/wp)) were systematically observed for the encapsulation of probes containing weak carboxylic acid groups by micellar nanoparticles having poly[2-(dialkylamino)ethyl methacrylate] cores (i.e., particles whose cargo space exhibits antagonist weak base functions), as demonstrated by the incorporation of indomethacin (IND), ibuprofen (IBPF), and trans-3,5-bis(trifluoromethyl)cinnamic acid (F-CIN) into either poly(ethylene oxide)-b-poly[2-(diisopropylamino)ethyl methacrylate] (PEO-b-PDPA) or poly(glycerol monomethacrylate)-b-PDPA (PG2MA-b-PDPA) micelles. The esterification of IND yielding to a nonionizable IND ethyl ester derivative (IND-Et) caused an abrupt decrease in the micellar loading capacity down to 10-15% w/wp. Similar results were also obtained when IND was combined with nonionizable block copolymers such as PEO-b-polycaprolactone (PEO-b-PCL) and PEO-b-poly(glycidyl methacrylate) (PEO-b-PGMA). The existence of acid-base interactions between the solubilizate and the weak polybase block forming the micelle core was confirmed by 1H NMR measurements. However, the incorporation of high numbers of hydrophobic guest molecules inside polymeric micelles can provoke not only an increase in the hydrodynamic size (2RH) of the objects but also a substantial change in the morphology (transition from spheres to cylinders). The application of the Higuchi model showed that the probe release followed a diffusion-controlled mechanism, and diffusion coefficients (D) on the order of 10-18-10-17 cm2/s were determined for IND release from 1.0 mg/mL PEO113-b-PDPA50 + 100% w/wp IND. Probe release from micelles with weak polybase-based cores can also be triggered by changes in the solution pH.
The synthesis, self-assembly behavior, and delivery properties of poly(ethylene oxide)-b-poly-(glycerol monomethacrylate)-(PEO-b-PG2MA-) drug conjugates is herein described. Double hydrophilic PEOb-PG2MA copolymers synthesized by atom transfer radical polymerization (ATRP), using a PEO-based macroinitiator, were used for post-polymerization conjugation to the hydrophobic nonsteroidal anti-inflammatory agent indomethacin (IND). IND contents ranging from 15 to 49% w/w p were attached to the same polymer precursor via Steglich esterification, leading to amphiphilic block copolymer-drug conjugates (PEO-b-(PG2MA-IND)). Dynamic light scattering (DLS) and transmission electron microscopy (TEM) experiments revealed that PEO-b-(PG2MA-IND) copolymer chains self-assemble into spherical nanoparticles in water, whose hydrodynamic size (2R H ) 24-100 nm) and morphology (micelles or vesicles) are dictated by both the amount of IND and the PG2MA block length. Interestingly, such a particular system was also proven to be able to stabilize, transport and deliver physically encapsulated (free) IND (F-IND). The maximum F-IND loadings ranged from 13 to 20% w/w p , thus reaching remarkable IND payloads (i.e., covalently bound B-IND + physically entrapped F-IND) as high as 58% w/w p . However, self-organization for F-IND loaded samples with more than 50% w/w p IND originated vesicular morphologies instead of micelles and provoked a huge increase in the size of the objects. The release of IND is a pH-dependent process, which is governed by intrinsic molecular characteristics of F-IND (aqueous dissociation behavior) and pH-sensitivity of ester linkages in the conjugates. At approximately neutral pH, the ester bound linkages are stable and the diffusion of F-IND out of the carrier is favored, whereas sustained release with slow kinetics takes place under acidic pH conditions.
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