Nanomaterials · 7 authors, 5 centres
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This review summarizes the use of polymer-based nanoparticles (e.g., PLGA, chitosan, dendrimers) to improve the delivery of purine drugs (e.g., acyclovir, tenofovir, 6-mercaptopurine). Key findings include enhanced drug retention, targeted delivery (e.g., to liver or brain), and reduced toxicity in animal models. The clinical significance lies in overcoming pharmacokinetic limitations of purine APIs, potentially improving therapies for viral infections, cancers, and autoimmune diseases.
**Background:** Many purine derivatives, such as acyclovir (ACV), tenofovir (TNF), 6-mercaptopurine (6-MP), and 6-thioguanine (6-TG), are important for treating viral infections, cancers, and autoimmune diseases. However, their clinical use is often limited by poor physicochemical and pharmacokinetic properties, including short half-life, low bioavailability, and toxicity. Polymer-based nanoparticles (NPs) offer a potential solution by improving drug delivery, retention, and targeting. This narrative review summarizes recent progress in polymer-based NP systems for purine drugs, focusing on PLGA, methacrylate copolymers, chitosan, gelatin, poly(ethyleneimine) (PEI), dendrimers, and polymeric micelles.
**Methods:** The authors conducted a narrative review of the literature, summarizing studies on polymer-based NPs loaded with purine APIs. They categorized NPs by polymer type (e.g., PLGA, chitosan, dendrimers) and discussed key findings from in vitro and in vivo studies, including pharmacokinetic parameters, cytotoxicity, and therapeutic efficacy. The review covers studies published up to the date of the paper (2021).
**Key Results:** - **PLGA NPs:** For 6-MP, PLGA NPs increased mean survival in rats from 23.5 days (free drug) to 51 days. For ACV, PLGA NPs with Pluronic F-127 extended mean residence time (MRT) 29-fold in rabbits. Galactosylated PLGA-ACV NPs increased liver concentration to 1207.93 μg/g vs. 124.30 μg/g for free drug. For tenofovir disoproxil (TDF), PLGA NPs in thermosensitive gel protected 100% of humanized mice from HIV-1 infection vs. controls. - **Chitosan NPs:** 6-MP chitosan NPs reduced acute toxicity (lethal dose >2000 mg/kg vs. <2000 mg/kg for free drug). Lactosaminated chitosan-ACV NPs extended MRT from 2.91 h to 19.67 h in mice. Intranasal chitosan-didanosine (DDI) NPs increased brain concentration to 42.37 ng/mL vs. 17.16 ng/mL for IV solution. - **Dendrimers:** Maltose-modified poly(propyleneimine) (PPI) dendrimers with fludarabine triphosphate bypassed resistance mechanisms in cancer cells. 6-MP in melamine dendrimers reduced hepatotoxicity (36% lower alanine aminotransferase). - **Polymeric Micelles:** 6-MP conjugated via disulfide bonds showed glutathione-dependent release (e.g., 65.1% release in 2 mM glutathione). 6-TG micelles reduced myeloid-derived suppressor cells in mice and increased efficacy of adoptively transferred T cells.
**Clinical Implications:** Polymer-based NPs significantly improve the pharmacokinetics and therapeutic index of purine drugs by enhancing bioavailability, prolonging retention, enabling targeted delivery (e.g., to liver, brain, or tumors), and reducing systemic toxicity. These systems hold promise for more effective and safer treatments for HIV, herpes simplex virus, leukemia, and autoimmune conditions. However, further in vivo and clinical studies are needed to validate efficacy and safety, as some carriers (e.g., cationic dendrimers) exhibit intrinsic toxicity. The review emphasizes that each drug-carrier combination must be individually optimized.