Conventional polymers may unintentionally refill in vivo with unassociated drugs

Abstract

Polymers used as drug delivery devices are ultimately limited by how much drug they can hold; with the device failing if the drug is depleted before the disease is cured. Our lab discovered a means to use thermodynamic driving forces to refill certain classes of polymer after implantation, for additional drug delivery windows. These same, refillable polymers can be used as additives, to provide refilling capacity to classical, non-refillable polymers such as poly(methyl methacrylate) (PMMA). In this paper, we investigated the refilling capacity of another conventional polymer: poly(lactic-co-glycolic acid) or PLGA. We explored both unmodified PLGA implants as well as implants supplemented with polymerized cyclodextrin (pCD) in microparticle form, previously shown to add refillability to poly(methyl methacrylate) (PMMA) implants which were otherwise not refillable. Assessments of in situ forming PLGA implants with and without pCD additives were made, including drug loading capacity in a liquid medium, drug refilling through a tissue-mimicking gel medium, and refilling in ex vivo and in vivo conditions. Implant cross-sections were imaged via fluorescence microscopy. Drug release from refilled implants, polymer swelling, degradation, phase inversion characteristics were assessed, and drug/monomer computational simulation studies were performed. While generally, the incorporation of cyclodextrin into implants led to significant increases in the amount of refilled drug; unexpectedly, PLGA implants with no incorporated pCD also showed refilling capability. Moreover, in two out of three in vivo conditions in rats, PLGA alone showed the potential to refill with comparable, if not greater, amounts of drug than PLGA with pCD incorporated. This contrasts predictions, since PLGA has no specifically designed affinity structure, like pCD does. We theorize that the mechanism for PLGAs refilling depends on nano-patterning of hydrophilic and hydrophobic molecular domains, giving rise to its affinity-like behavior. The fact that PLGA implants can be refilled with unassociated drugs, gives rise to concerns about the fate of all implants made of poly alpha-hydroxy esters, and likely other polymers as well, and will likely lead to new directions of study such as of unintended polymer / drug interactions.