A Highly Translatable Dual‐arm Local Delivery Strategy To Achieve Widespread Therapeutic Coverage in Healthy and Tumor‐bearing Brain Tissues

Abstract

Drug delivery nanoparticles (NPs) based entirely on materials generally recognized as safe that provide widespread parenchymal distribution following intracranial administration via convection‐enhanced delivery (CED) are introduced. Poly(lactic‐co‐glycolic acid) (PLGA) NPs are coated with various poloxamers, including F68, F98, or F127, via physical adsorption to render particle surfaces non‐adhesive, thereby resisting interactions with brain extracellular matrix. F127‐coated PLGA (F127/PLGA) NPs provide markedly greater distribution in healthy rat brains compared to uncoated NPs and widespread coverage in orthotopically‐established brain tumors. Distribution analysis of variously‐sized F127/PLGA NPs determines the average rat brain tissue porosity to be between 135 and 170 nm while revealing unprecedented brain coverage of larger F127/PLGA NPs with an aid of hydraulic pressure provided by CED. Importantly, F127/PLGA NPs can be lyophilized for long‐term storage without compromising their ability to penetrate the brain tissue. Further, 65‐ and 200‐nm F127/PLGA NPs lyophilized‐reconstituted and administered in a moderately hyperosmolar infusate solution show further enhance particle dissemination in the brain via osmotically‐driven enlargement of the brain tissue porosity. Combination of F127/PLGA NPs and osmotic tissue modulation provides a means with a clear regulatory path to maximize the brain distribution of large NPs that enable greater drug loading and prolong drug release.

Strategic Assessment of Boron-Enriched Carbon Dots/Naproxen: Diagnostic, Toxicity, and In Vivo Therapeutic Evaluation

“…21−24 Drug loading processes encompass physical and chemical approaches, where physical encapsulation offers simplicity and cost-effectiveness but may suffer from offtargeted molecular degradation. 25,26 Conversely, chemical conjugation with polymer materials provides advantages such as hydrophobic drug solubility, controlled pharmacokinetics, and reduced drug release in large quantities. 27,28 A previous study evaluated tetrazine-functionalized boron-rich carbon dots, which demonstrated rapid clearance and low tumor absorption following intravenous administration in a mouse HER2-positive tumor model.…”

“…In the face of the ongoing investigation into toxicity, the integration of nanoparticles into drug delivery systems remains achievable through active or passive targeting mechanisms. − Drug loading processes encompass physical and chemical approaches, where physical encapsulation offers simplicity and cost-effectiveness but may suffer from off-targeted molecular degradation. , Conversely, chemical conjugation with polymer materials provides advantages such as hydrophobic drug solubility, controlled pharmacokinetics, and reduced drug release in large quantities. , A previous study evaluated tetrazine-functionalized boron-rich carbon dots, which demonstrated rapid clearance and low tumor absorption following intravenous administration in a mouse HER2-positive tumor model . Naproxen, a widely recognized nonsteroidal anti-inflammatory drug (NSAID), has recently garnered attention for its potential anticancer properties, as evidenced by its efficacy as a COX-2 inhibitor in clinical trials. − Our previous study proved that a combination of naproxen with nanoparticles results in better activity regarding the treatment of several diseases. − Despite these promising properties, there is limited research on the kinetic release model that typically occurs when B-CDs are combined with anticancer medications, both in vitro and in vivo.…”