Doxorubicin Conjugation and Drug Linker Chemistry Alter the Intravenous and Pulmonary Pharmacokinetics of a PEGylated Generation 4 Polylysine Dendrimer in Rats

Abstract

PEGylated polylysine dendrimers have demonstrated potential as inhalable drug delivery systems that can improve the treatment of lung cancers. Their treatment potential may be enhanced by developing constructs that display prolonged lung retention, together with good systemic absorption, the capacity to passively target lung tumors from the blood and highly selective, yet rapid liberation in the tumor microenvironment. This study sought to characterize how the nature of cathepsin B-cleavable peptide linkers, used to conjugate doxorubicin (Dox) to a PEGylated (PEG570) G4 polylysine dendrimer, affects drug liberation kinetics and intravenous and pulmonary pharmacokinetics in rats. The construct bearing a self-emolative diglycolic acid-V-Citrulline linker exhibited faster Dox release kinetics compared to constructs bearing self-emolative diglycolic acid-glycine-leucine-phenylalanine-glycine (GLFG), or non-self-emolative glutaric acid-GLFG linkers. The V-Citrulline construct exhibited slower plasma clearance, but faster absorption from the lungs than a GLFG construct, although mucociliary clearance and urinary elimination were unchanged. Dox-conjugation enhanced localization in the bronchoalveolar lavage fluid compared to lung tissue, suggesting that projection of Dox from the dendrimer surface reduced tissue uptake. These data show that the linker chemistry employed to conjugate drugs to PEGylated carriers can affect drug release profiles and systemic and lung disposition.

Inhalable nanotherapeutics to improve treatment efficacy for common lung diseases

“…In a MAT 13762 IIIB breast metastasized lung cancer model in female F334 rats, twice weekly administration (either IV or IT administration) of D‐DOX or free DOX showed a >95% tumor burden reduction after 2 weeks for IT D‐DOX compared to the IV DOX which averaged around a 30–50% reduction; inhalation of free DOX solution lead to extensive lung‐related toxicity and death. Their results suggest that this dendrimer system as an inhalable drug delivery system prolongs chemotherapy drug exposure to lung‐resident cancers and improves overall anticancer therapeutic efficacy, and this group has further highlighted the advantages of this system with other animal models as well (Kaminskas et al, ; Leong et al, ; Ryan et al, ).…”

Highly Branched Polymers Based on Poly(amino acid)s for Biomedical Application

“…The group of Kaminskas has contributed significant insight into the use of p( L -Lys)-based dendrimers as drug delivery systems in general [ 48 , 49 , 50 , 51 , 52 ] and inhalable systems in particular [ 53 , 54 , 55 , 56 , 57 ]. The inhalability of dendrimer-based delivery systems is of particular interest to the treatment of lung diseases.…”

Dendrimers: Amazing Platforms for Bioactive Molecule Delivery Systems

“…The results show that PEGylated polylysine dendrimers have great potential as inhalable chemotherapeutic nanoformulations, improving the exposure of lung tumor to a cytotoxic drug [106]. Likewise, conjugates of DOX linked to PEGylated G4-polylysine dendrimer were studied to determine drug delivery kinetics, intravenous, and pulmonary pharmacokinetics in rats [107]. Cathepsin B-cleavable peptides were used to drug-linker since the extracellular and lysosomal expression of this enzyme is highly upregulated by cancer cells.…”