Tuning the In Vivo Transport of Anticancer Drugs Using Renal‐Clearable Gold Nanoparticles

Abstract

Precise control of in vivo transport of anticancer drugs in normal and cancerous tissues with engineered nanoparticles is key to the future success of cancer nanomedicines in clinics.T his requires af undamental understanding of how engineered nanoparticles impact the targeting-clearance and permeation-retention paradoxes in the anticancer-drug delivery.Herein, we systematically investigated how renal-clearable gold nanoparticles (AuNPs) affect the permeation, distribution, and retention of the anticancer drug doxorubicin in both cancerous and normal tissues.R enal-clearable AuNPs retain the advantages of the free drug, including rapid tumor targeting and high tumor vascular permeability.T he renal-clearable AuNPs also accelerated body clearance of off-target drug via renal elimination. These results clearly indicate that diverse in vivo transport behaviors of engineered nanoparticles can be used to reconcile long-standing paradoxes in the anticancer drug delivery.Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.

Renal Clearable Theranostic Nanoplatforms for Gastrointestinal Stromal Tumors

“…Very recently, ultrasmall silica NPs (<10 nm in diameter) were reported by Bradbury and coworkers and were applied as a drug delivery vehicle for inducing ferroptosis and regression of tumor . In addition to silica NPs, the Zheng group has intensively studied renal clearable ultrasmall gold NPs (<2 nm core diameter) to target tumors and deliver the anticancer drug, doxorubicin . Previously, we also reported that an ultrasmall (<5.5 nm) zwitterionic organic nanocarrier, termed Harvard‐Dot or H‐Dot, systemically travels the whole body through the bloodstream without nonspecific tissue uptake, then eventually clears out to the urine exclusively (>80% at 4 h postinjection) .…”

“…After the distribution phase, renal clearable NPs are rapidly cleared from the major organs through urinary excretion resulting in less background retention in organs and tissues . Due to very low background tissue retention, renal clearable NPs can exhibit a high tumor‐to‐background signal ratio for tumor targeting via the enhanced permeability and retention (EPR) effect, despite the lack of active targeting moieties 9a,c. On the other hand, nonrenal clearable and nonspecific NPs, which are mostly larger in size and/or lipophilic, are retained in the central and peripheral compartments including immune‐related organs such as the liver and spleen 7a,12.…”

Correlating Anticancer Drug Delivery Efficiency with Vascular Permeability of Renal Clearable Versus Non‐renal Clearable Nanocarriers

“…[12b] We also used renal clearable AuNPs to deliver awidely used anticancer drug, doxorubicin (DOX), to primary and lung metastatic breast cancers and compared the differences in the tumor targeting and clearance of DOXwith or without being loaded into renal clearable AuNPs. [13] We found that renal clearable AuNPs not only enhanced tumor targeting efficiency and efficacy of DOX but also accelerated clearance of off-target DOX; so that the long-standing targeting-clearance paradox in the anticancer drug delivery was successfully addressed. [13] However,t here are still many fundamental questions regarding differences in the anticancer drug delivery between these renal clearable DDSs and conventional non-renal clearable ones.While renal clearable DDSs are known to be highly permeable to both tumor and normal vasculatures and have much shorter blood retention than conventional nano-DDSs,aquantitative and thorough investigation is highly desired to understand how the high vascular permeability of renal clearable DDSs impacts the intratumoral transport and therapeutic efficacyofanticancer drugs over conventional non-renal clearable ones.…”

“…[13] We found that renal clearable AuNPs not only enhanced tumor targeting efficiency and efficacy of DOX but also accelerated clearance of off-target DOX; so that the long-standing targeting-clearance paradox in the anticancer drug delivery was successfully addressed. [13] However,t here are still many fundamental questions regarding differences in the anticancer drug delivery between these renal clearable DDSs and conventional non-renal clearable ones.While renal clearable DDSs are known to be highly permeable to both tumor and normal vasculatures and have much shorter blood retention than conventional nano-DDSs,aquantitative and thorough investigation is highly desired to understand how the high vascular permeability of renal clearable DDSs impacts the intratumoral transport and therapeutic efficacyofanticancer drugs over conventional non-renal clearable ones. [14] Herein, we conducted ahead-to-head comparison on the differences in the tumor accumulation, intratumoral transport, and therapeutic index of DOX delivered by 5nmrenal clearable and 30 nm non-renal clearable AuNP-based DDSs, which had comparable tumor targeting efficiency but distinct elimination pathways.Our findings show that renal clearable AuNPs can enhance tumor accumulation, efficacy, and therapeutic index of DOX 2, 7, and 10-fold, respectively, over non-renal clearable AuNPs,e ven though their blood retention is two-fold lower than non-renal clearable ones.…”

“…Moreover,D OX carried by DDS-5 showed am ore rapid body distribution (volume of distribution, Vd, of 15.4 mL and distribution half-life, T 1/2a ,of 0.24 h) than that by the DDS-30 (Vd of 9.0 mL and T 1/2a of 0.42 h, Figure S7), consistent with our observation that DOX targeted the tumor more rapidly after being loaded onto DDS-5. [13] Since DDS-5 had higher tumor delivery,m ore rapid renal excretion, and lower background retention than DDS-30, the renal clearable DDS-5 showed much higher tumor selectivity or tumor-to-background [12a] ratio compared to the non-renal clearable counterpart. These findings also indicate that neither the tumor targeting efficiency of these two nanocarriers nor the blood retention of DOX plays the major role in the DOX delivery.…”