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INTRODUCTION: Implantable devices can be designed to release drugs to localized regions of tissue at sustained and reliable rates. Advances in polymer engineering have led to the design and development of drug-loaded implants with predictable, desirable release profiles. Biodegradable polyesters exhibit chemical, physical, and biological properties suitable for developing implants for pain management, cancer therapy, contraception, antiviral therapy, and other applications. AREAS COVERED: This article reviews the use of biodegradable polyesters for drug-loaded implants by discussing the properties of commonly used polymers, techniques for implant formulation and manufacturing, mechanisms of drug release, and clinical applications of implants as drug delivery devices. EXPERT OPINION: Drug delivery implants are unique systems for safe and sustained drug release, providing high bioavailability and low toxicity. Depending on the implant design and tissue site of deployment, implants can offer either localized or systemic drug release. Due to the long history of use of degradable polyesters in medical devices, polyester-based implants represent an important class of controlled release technologies. Further, polyester-based implants are the largest category of drug delivery implants to reach the point of testing in humans or approval for human use.
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Poliésteres , Polímeros , Humanos , Preparações de Ação Retardada , Implantes de Medicamento/química , Liberação Controlada de Fármacos , Sistemas de Liberação de Medicamentos/métodosRESUMO
Poly(ethylene glycol) (PEG) is widely employed for passivating nanoparticle (NP) surfaces to prolong blood circulation and enhance localization of NPs to target tissue. However, the immune response of PEGylated NPs-including anti-PEG antibody generation, accelerated blood clearance (ABC), and loss of delivery efficacy-is of some concern, especially for treatments that require repeat administrations. Although polyglycerol (PG), which has the same ethylene oxide backbone as PEG, has received attention as an alternative to PEG for NP coatings, the pharmacokinetic and immunogenic impact of PG has not been studied systematically. Here, linear PG, hyperbranched PG (hPG), and PEG-coated polylactide (PLA) NPs with varying surface densities were studied in parallel to determine the pharmacokinetics and immunogenicity of PG and hPG grafting, in comparison with PEG. We found that linear PG imparted the NPs a stealth property comparable to PEG, while hPG-grafted NPs needed a higher surface density to achieve the same pharmacokinetic impact. While linear PG-grafted NPs induced anti-PEG antibody production in mice, they exhibited minimal accelerated blood clearance (ABC) effects due to the poor interaction with anti-PEG immunoglobulin M (IgM). Further, we observed no anti-polymer IgM responses or ABC effects for hPG-grafted NPs.
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Among the various catalysts for ROP, H-bonding organocatalysts stand out in the precise level of reaction control they are able to render during ROP. The H-bonding class of organocatalysts are thought to effect ROP via dual activation of both monomer and chain end. (Thio)urea mediated ROP has experienced a renaissance as a new polymerization mechanism - mediated by imidate or thioimidate species - facilitates new modes of reactivity and new synthetic abilities. Indeed, the urea class of H-bond donors has been shown to be more active than their corresponding thioureas. The imidate mechanism remains highly active in polar solvents and exhibits remarkable control - and 'living' behavior - under solvent-free conditions, and a broad range of temperatures is accessible. The advancements in synthetic abilities have all evolved through a greater understanding of reaction mechanism. Through the continued synergistic advances of catalysis and material, the (thio)urea class of catalyst can find use in a host of potential applications, research and industrial environments.
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The antibacterial compound, triclocarban (TCC), is shown to be a highly effective H-bond donating catalyst for ring-opening polymerization (ROP) when applied with an H-bond accepting base cocatalyst. These ROPs exhibit the characteristics of "living" polymerizations. TCC is shown to possess the high activity characteristic of urea (vs thiourea) H-bond donors. The urea class of H-bond donors is shown to remain highly active in H-bonding solvents, a trait that is not displayed by the corresponding thiourea H-bond donors. Two H-bond donating ureas that are electronically similar to TCC are evaluated for their efficacy in ROP, and a mechanism of action is proposed. This "off-the-shelf" H-bond donor is among the most active and most controlled organocatalysts for the ROP of lactones.
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A new class of H-bond donating ureas was developed for the ring-opening polymerization (ROP) of lactone monomers, and they exhibit dramatic rate acceleration versus previous H-bond mediated polymerization catalysts. The most active of these new catalysts, a tris-urea H-bond donor, is among the most active organocatalysts known for ROP, yet it retains the high selectivity of H-bond mediated organocatalysts. The urea cocatalyst, along with an H-bond accepting base, exhibits the characteristics of a "living" ROP, is highly active, in one case, accelerating a reaction from days to minutes, and remains active at low catalyst loadings. The rate acceleration exhibited by this H-bond donor occurs for all base cocatalysts examined. A mechanism of action is proposed, and the new catalysts are shown to accelerate small molecule transesterifications versus currently known monothiourea catalysts. It is no longer necessary to choose between a highly active or highly selective organocatalyst for ROP.