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Encapsulation and Controlled Release of a Camptothecin Prodrug from Nanocarriers and Microgels: Tuning Release Rate with Nanocarrier Excipient Composition. | LitMetric

AI Article Synopsis

Article Abstract

Nanocarriers (NCs) are an attractive class of vehicles for drug delivery with the potential to improve drug efficacy and safety, particularly for intravenous parenteral delivery. Many therapeutics remain challenging to formulate in NCs due to their intrinsic solubilities that frustrate NC loading or result in too rapid release . Therapeutic conjugate approaches that alter the solubility of a conjugate "prodrug" have been used to enable NC formation and controlled release from NCs using labile linker chemistry. A limitation of this approach has been that a different linker chemistry must be used to produce an adjustable release rate for a single therapeutic. We report on a new approach where the therapeutic conjugate hydrolysis rates are varied by adjusting the excipient formulation of the NC core, not the conjugate linker chemistry. A hydrophobic therapeutic conjugate of camptothecin (PROCPT) is synthesized by conjugating camptothecin (CPT) with an acid derivative of α-tocopherol (vitamin E). The PROCPT compound can be loaded to 50% wt in poly(lactic acid)--poly(ethylene glycol) (PLA--PEG)-stabilized NCs produced by Flash NanoPrecipitation with particle diameters between 60 and 80 nm. Co-loading a zwitterionic lipid, 1-palmitoyl-2-oleoyl--3-phosphocholine, from 0 to 67% core loading tunes the PROCPT hydrolysis from no observable therapeutic release over 200 h to therapeutic conjugate half-life times of 31 h. For a single therapeutic conjugate molecule, the hydrolysis rate can be tuned by modifying the NC formulation with different excipient concentrations. NCs containing a 50% core loading of PROCPT were lyophilized and encapsulated in a PEG hydrogel matrix to make microparticles for depot delivery with an average diameter of 65 ± 10 μm that provide a sustained, first-order release of CPT with a therapeutic conjugate half-life of 240 h. These results demonstrate a new approach to the formulation of therapeutic NCs with variable release profiles using a single molecular entity therapeutic conjugate.

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Source
http://dx.doi.org/10.1021/acs.molpharmaceut.0c01012DOI Listing

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