A Nanoparticle's Journey to the Tumor: Strategies to Overcome First-Pass Metabolism and Their Limitations

Simple Summary Traditional cancer therapeutics suffer from off-target toxicity, limiting their effective dose and preventing patients' tumors from being sufficiently treated by chemotherapeutics alone. Nanomedicine is an emerging class of therapeutics in which a drug is packaged into a nanoparticle that promotes uptake of the drug at a tumor site, shielding it from uptake by peripheral organs and enabling the safe delivery of chemotherapeutics that have poor aqueous solubility, short plasma half-life, narrow therapeutic window, and toxic side effects. Despite the advantages of nanomedicines for cancer, there remains significant challenges to improve uptake at the tumor and prevent premature clearance from the body. In this review, we summarize the effects of first-pass metabolism on a nanoparticle's journey to a tumor and outline future steps that we believe will improve the efficacy of cancer nanomedicines. Nanomedicines represent the cutting edge of today's cancer therapeutics. Seminal research decades ago has begun to pay dividends in the clinic, allowing for the delivery of cancer drugs with enhanced systemic circulation while also minimizing off-target toxicity. Despite the advantages of delivering cancer drugs using nanoparticles, micelles, or other nanostructures, only a small fraction of the injected dose reaches the tumor, creating a narrow therapeutic window for an otherwise potent drug. First-pass metabolism of nanoparticles by the reticuloendothelial system (RES) has been identified as a major culprit for the depletion of nanoparticles in circulation before they reach the tumor site. To overcome this, new strategies, materials, and functionalization with stealth polymers have been developed to improve nanoparticle circulation and uptake at the tumor site. This review summarizes the strategies undertaken to evade RES uptake of nanomedicines and improve the passive and active targeting of nanoparticle drugs to solid tumors. We also outline the limitations of current strategies and the future directions we believe will be explored to yield significant benefits to patients and make nanomedicine a promising treatment modality for cancer.