Sustained Intracellular Raltegravir Depots Generated with Prodrugs Designed for Nanoparticle Delivery

Abstract

Polymeric nanocarriers have been extensively used to improve the delivery of hydrophobic drugs, but often provide low encapsulation efficiency and percent loading for hydrophilic compounds. In particular, insufficient loading of hydrophilic antiretroviral drugs such as the integrase inhibitor raltegravir (RAL) has limited the development of sustained-release therapeutics or prevention strategies against HIV. To address this, we developed a generalizable prodrug strategy using RAL as a model where loading, release and subsequent hydrolysis can be tuned by promoiety selection. Prodrugs with large partition coefficients increased the encapsulation efficiency up to 25-fold relative to RAL, leading to significant dose reductions in antiviral activity assays. The differential hydrolysis rates of these prodrugs led to distinct patterns of RAL availability and observed antiviral activity. We also developed a method to monitor the temporal distribution of both prodrug and RAL in cells treated with free prodrug or prodrug-NPs. Results of these studies indicated that prodrug-NPs create an intracellular drug reservoir capable of sustained intracellular drug release. Overall, our results suggest that the design of prodrugs for specific polymeric nanocarrier systems could provide a more generalized strategy to formulate physicochemically diverse hydrophilic drugs with a number of biomedical applications.

Matrix-Assisted Laser Desorption and Electrospray Ionization Tandem Mass Spectrometry of Microbial and Synthetic Biodegradable Polymers

“…ESI tandem MS has been used more extensively than MALDI-MS/MS in the analysis of biodegradable polymers. In the literature, ESI-MS/MS studies concern fragmentation analysis and insights on comparative dissociation tools [ 50 , 51 , 53 , 55 , 82 ], structural characterization [ 19 , 55 , 63 , 64 , 65 , 67 , 68 , 70 , 71 , 72 , 74 , 75 , 80 , 81 , 83 , 86 , 121 , 122 , 123 , 124 , 125 , 126 ], drug delivery systems [ 89 , 90 , 91 , 95 , 96 , 97 , 98 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 ] and degradation studies [ 111 , 112 , 113 , 114 , 115 , …”

“…Chromatographic separation combined with tandem MS has been more and more recurrently used in the assessment of biodegradable DDS, such as microspheres, micelles, or nanoparticles, measuring drug loading or concentration [ 97 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 111 , 112 ] and monitoring drugs or hormone release, in vitro and in vivo [ 89 , 90 , 91 , 95 , 96 , 102 , 110 , 111 ]. Recently, Ultra-HPLC (UHPLC) with MS/MS methods has been developed, attracting considerable interest in pharmacokinetic studies for its high sensitivity, accuracy, and precision.…”

“…ESI tandem MS has been used more extensively than MALDI-MS/MS in the analysis of biodegradable polymers. In the literature, ESI-MS/MS studies concern fragmentation analysis and insights on comparative dissociation tools [50,51,53,55,82], structural characterization [19,55,[63][64][65]67,68,[70][71][72]74,75,80,81,83,86,[121][122][123][124][125][126], drug delivery systems [89][90][91][95][96][97][98][100][101][102][103][104][105][106][107][108][109][110][111][112] and degradation studies [111]…”

Synthesis and antiviral activity of fatty acyl conjugates of remdesivir against severe acute respiratory syndrome coronavirus 2 and Ebola virus

“…Similar results were obtained using a 5′- O -myristoyl conjugate of 3TC where a long-acting nanoformulation of a fatty acyl conjugate of 3TC was shown to reduce hepatitis B virus replication in humanized mice [ 23 ]. Additionally, Creighton et al demonstrated that fatty acid conjugation with raltegravir tuned its release pattern, hydrolysis rate, and anti-HIV activity [ 24 ]. Overall, the studies revealed that the prodrug action was dependent on the type of conjugated fatty acid and the position of the conjugation of fatty acid to the drug.…”

Prodrug-based nano-delivery strategy to improve the antitumor ability of carboplatin in vivo and in vitro

“…However, the high water-solubility makes platinum hard to be encapsulated into nanoparticles efficiently (Ita, 2016 ; Arduino et al., 2020 ). Thus, the chemical conjugate based prodrug (Gu et al., 2019 ) is confirmed to be one of the most potential routes to improve the poor therapeutic effect of platinum, and now become a hot area of research (Feazell et al., 2007 ; Rieter, et al., 2008 ; Dhar et al., 2011 ; Li et al., 2012 ; Butler & Sadler, 2013 ; Kumar et al., 2014 ; Creighton et al., 2019 ). This is because that the prodrug platinum (IV) complexes usually have low spin d 6 selective configuration and octahedral geometry (Li et al., 2018 ; Liu et al., 2019 ; Chen et al., 2020 ), which endow them with high kinetic inertia to substitution (Graf & Lippard, 2012 ).…”