Total drug quantification in prodrugs using an automated elemental analyzer.

Polymeric prodrugs have become an increasingly popular strategy for improving the pharmacokinetic properties of active pharmaceutical ingredients (API). Therefore, identifying a robust method for quantification of the API in these prodrug products is a key part of the drug development process. Current drug quantification methods include hydrolysis followed by reversed phase high-performance liquid chromatography (RP-HPLC), size exclusion chromatography (SEC)-based molecular weight determination, and mass spectrometry. These methods tend to be time-consuming and often require challenging method development. Here, we present a comparative study highlighting the automated elemental analyzer as a facile approach to drug quantification in this up-and-coming class of therapeutics. A polymeric prodrug using poly(L-lysine succinylated) (PLS) and the drug lamivudine (LAM) was prepared and analyzed using the elemental analyzer in comparison to the traditional approaches of hydrolysis followed by RP-HPLC and SEC using multi-angle light scattering (MALS) detection. The elemental analysis approach showed excellent agreement with the conventional methods but proved much less laborious, highlighting this as a rapid and sensitive analytical method for the quantitative determination of drug loading in polymeric prodrug products.

Protein corona composition does not accurately predict hematocompatibility of colloidal gold nanoparticles.

Proteins bound to nanoparticle surfaces are known to affect particle clearance by influencing immune cell uptake and distribution to the organs of the mononuclear phagocytic system. The composition of the protein corona has been described for several types of nanomaterials, but the role of the corona in nanoparticle biocompatibility is not well established. In this study we investigate the role of nanoparticle surface properties (PEGylation) and incubation times on the protein coronas of colloidal gold nanoparticles. While neither incubation time nor PEG molecular weight affected the specific proteins in the protein corona, the total amount of protein binding was governed by the molecular weight of PEG coating. Furthermore, the composition of the protein corona did not correlate with nanoparticle hematocompatibility. Specialized hematological tests should be used to deduce nanoparticle hematotoxicity. From the clinical editor: It is overall unclear how the protein corona associated with colloidal gold nanoparticles may influence hematotoxicity. This study warns that PEGylation itself may be insufficient, because composition of the protein corona does not directly correlate with nanoparticle hematocompatibility. The authors suggest that specialized hematological tests must be used to deduce nanoparticle hematotoxicity.

Inhibition of phosphoinositol 3 kinase contributes to nanoparticle-mediated exaggeration of endotoxin-induced leukocyte procoagulant activity.

AIM: Disseminated intravascular coagulation is an increasing concern for certain types of engineered nanomaterials. Recent studies have shed some light on the nanoparticle physicochemical properties contributing to this toxicity; however, the mechanisms are poorly understood. Leukocyte procoagulant activity (PCA) is a key factor contributing to the initiation of this toxicity. We have previously reported on the exaggeration of endotoxin-induced PCA by cationic dendrimers. Herein, we report an effort to discern the mechanism. MATERIALS & METHODS: Poly(amidoamine) dendrimers with various sizes and surface functionalities were studied in vitro by the recalcification test, flow cytometry and other relevant assays. RESULTS & CONCLUSION: Cationic dendrimers exaggerated endotoxin-induced PCA, but their anionic or neutral counterparts did not; the cationic charge prompts this phenomenon, but different cationic surface chemistries do not influence it. Cationic dendrimers and endotoxin differentially affect the PCA complex. The inhibition of phosphoinositol 3 kinase by dendrimers contributes to the exaggeration of the endotoxin-induced PCA.

Synthesis of Polyglycerol, Porphyrin-Cored Dendrimers Using Click Chemistry.

Polyglycerol, porphyrin-cored dendrimers were synthesized by the click reaction of azide-cored polyglycerol dendrons and octaazidoporphyrin 19. The dendrons were synthesized divergently starting with TBDPS protected allyl alcohol 2. Two, three and four cycles of dihydroxylation-allyl etherification gave dendrons [G-2.5] 6, [G-3.5] 8, [G-4.5] 11, with four, eight, and sixteen alkene groups, respectively. Dendron 11 was readily prepared on large scale with an overall yield of 45%. Dendron 8 was deprotected and converted to the corresponding alkyne - and azide-cored dendron 13 and 15 in 89% and 75% yield, respectively. Dendron 11 was deprotected and converted to the corresponding alkyne - and azide-cored dendron 16 and 18 in 68% and 24% yield, respectively. Both the [G-3.5]-azide 15 and [G-4.5]-azide 18 were separately "clicked" to polyalkyne core 19 via the Huisgen 1,3-dipolar cycloaddition to afford 20 and 21 in 65% and 66% yield, respectively. Dendrimer 21 has a MW ~ 16,000 and 128 peripheral alkene groups.