Efficient Anticancer Drug Delivery Research Articles

Hierarchical Fabrication of DNA Wireframe Nanoarchitectures for Efficient Cancer Imaging and Targeted Therapy.

Though small-molecule drugs play a crucial role in cancer treatment, intrinsic issues such as poor solubility and systematic toxicity have considerably mitigated their anticancer functions and caused unwanted side effects. To achieve satisfying therapeutic efficiency, it is essential to develop innovative targeting systems for precise and efficient delivery of anticancer drugs. In this work, a hierarchical self-assembly strategy was applied to fabricate a core-shell nanoarchitecture composed of a DNA octahedral wireframe and chemodrug-functionalized Sgc8c aptamer. The integrated enhanced permeability and retention effect of the DNA nanostructure and active targeting ability of the Sgc8c aptamer allowed the highly selective chemodrug delivery and in vivo efficient imaging and treatment. The advantage of our multifunctional nanostructure was further highlighted by its impressive serum stability, excellent accumulation ability, deep penetration capability, significantly improved therapeutic efficacy, and favorable biosafety. This study showed promising potential of such a core-shell DNA nanoarchitecture in precise drug loading control, drug delivery, and personal medicine.

Chitosan-Modified Silver Nanoparticles Enhance Cisplatin Activity in Breast Cancer Cells

Cancer therapy has been hindered by treatments lacking sensitivity, specificity, and affordability. The side effects of conventional chemotherapy enforce the need for a treatment strategy that would maximize the anti-cancer activity of the drug while minimizing its’ adverse effects on healthy cells. Nanoparticles (NPs) as carriers for anti-cancer drugs have attracted interest due to their favorable properties, which include the enhanced permeability and retention effect. Silver NPs (AgNPs) have been explored as nanocarriers owing to their good conductivity, chemical stability, and therapeutic potential. In this study, AgNPs were synthesized, functionalized with chitosan (CS), and loaded with the anti-cancer drug cisplatin (CIS). Successful conjugation, size distribution, and morphology of the NPs were assessed by UV-vis and Fourier transform infra-red (FTIR) spectroscopy, NP tracking analysis (NTA), and transmission electron microscopy (TEM). The encapsulated CIS (>80%) was efficiently and rapidly released from the nanocomplex at low pH, favoring delivery to a tumor micro-environment. Cytotoxicity profiles of the CS-AgNP-CIS nanocomplexes exhibited significant cell death in the human breast cancer cell lines, MCF-7 and SKBR-3. They were more effective than the free drug, exhibiting >50% cell death. Our results demonstrate a potentially efficient anti-cancer drug delivery system with selectivity to breast cancer cells.

Application of smart solid lipid nanoparticles to enhance the efficacy of 5-fluorouracil in the treatment of colorectal cancer

5-Fluorouracil (5-FU) is a standard treatment option for colorectal cancer (CRC) but its rapid metabolism and systemic instability (short half-life) has hindered its therapeutic efficacy. The objective of this study was to develop a novel drug delivery system, solid lipid nanoparticle (SLN), capable of delivering high payload of 5-FU to treat CRC. The rational was to improve 5FU-nanocarrier compatibility and therapeutic efficacy. The SLN-loaded 5-FU was developed by utilizing a Strategic and unique Method to Advance and Refine the Treatment (SMART) of CRC through hot and cold homogenization approach. The SLN was made of unique PEGylated lipids and combination of the surfactants. Cytotoxicity studies, clonogenic assay, flow cytometry and confocal imaging were conducted to evaluate the effectiveness and cellular uptake of 5FU-SLN4 in HCT-116 cancer cells. Pharmacokinetic (PK) parameters and receptor expressions were determined while tumor efficacy studies were conducted on mouse bearing subcutaneous HCT-116 cancer. Among the all the formulations, 5FU-SLN4 was the most effective with particle size of was 263 ± 3 nm, zeta potential was 0.1 ± 0.02 and entrapment efficiency of 81 ± 10%. The IC50 value of 5FU-SLN4 (7.4 ± 0.02 µM) was 2.3 fold low compared with 5-FU (17.7 ± 0.03 µM). For tumor efficacy studies, 5FU-SLN4 significantly inhibited tumor growth in comparison to 5-FU while area-under plasma concentration-time curve (AUC) of 5FU-SLN4 was 3.6 fold high compared with 5-FU. HER2 receptors expression were markedly reduced in 5-FU-SLN4 treated mice compared with 5FU and liver and kidney tissues showed no toxicity at dose of 20 mg/kg. 5FU-SLN4 was highly cytotoxic against HCT-116 cells and significantly inhibited subcutaneous tumor growth in mice compared with 5-FU. This emphasizes the significance of developing a smart nano-delivery system to optimize the delivery efficiency of anticancer drugs to tumors.

Electrospun polyacrylonitrile/cellulose acetate/MIL-125/TiO2 composite nanofibers as an efficient photocatalyst and anticancer drug delivery system

In the present study, the various amounts of MIL-125-NH2 metal organic framework (MOF)/TiO2 nanocomposite were incorporated into the polyacrylonitrile (PAN)/cellulose acetate (CA) (8:2 w/w) nanofibers. The performance of MIL-125-NH2/TiO2 nanocomposite loaded-PAN/CA nanofibers was investigated for the removal of Doxorubicin HCl (DOX) and Cr(VI) during photocatalysis/adsorption method, controlled release of DOX and MCF-7 breast cancer cells death in vitro. The synthesized MIL-125-NH2 MOF, TiO2, MOF/TiO2 and MOF/TiO2 loaded-nanofibers were characterized using X-ray diffraction, scanning electron microscopy, Fourier transform infrared, transmission electron microscopy, and Brunaure–Emmet–Teller analysis. The effect of MOF to TiO2 weight ratio, MOF/TiO2 content, pH, contact time, catalyst dosage, and initial concentrations of DOX and Cr(VI) solutions was evaluated on the photocatalytic removal of DOX molecules and Cr(VI) ions from aqueous solutions. The maximum monolayer adsorption capacity of synthesized PAN/CA//MIL-125-NH2/TiO2 nanofibers was found to be 244.5 and 273.3 mg g−1 for DOX and Cr(VI) sorption, respectively. The reusability of nanofibers was also examined after five runs. The sustained release of DOX from PAN/CA/MIL-125-NH2/TiO2 was obtained during 7 days. The maximum MCF-7 cells death percentage was found to be 68% in the presence of PAN/CA/MIL-125-NH2/TiO2 nanofibers.

Overcoming anticancer resistance by photodynamic therapy-related efflux pump deactivation and ultrasound-mediated improved drug delivery efficiency

One of the major obstacles to successful chemotherapy is multi-drug resistance (MDR). A multi-drug resistant cancerous cell abnormally overexpresses membrane transporters that pump anticancer drugs out of the cell, resulting in low anticancer drug delivery efficiency. To overcome the limitation, many attempts have been performed to inhibit the abilities of efflux receptors chemically or genetically or to increase the delivery efficiency of anticancer drugs. However, the results have not yet been satisfactory. In this study, we developed nanoparticle-microbubble complexes (DOX-NPs/Ce6-MBs) by conjugating doxorubicin loaded human serum albumin nanoparticles (DOX-NPs) onto the surface of Chlorin e6 encapsulated microbubbles (Ce6-MBs) in order to maximize anticancer efficiency by overcoming MDR. Under the ultrasound irradiation, DOX-NPs and Ce6 encapsulating self-assembled liposomes or micelles were effectively delivered into the cells due to the sonoporation effect caused by the microbubble cavitation. At the same time, reactive oxygen (ROS) generated from intracellularly delivered Ce6 by laser irradiation arrested the activity of ABCG2 efflux receptor overexpressed in doxorubicin-resistant breast cancer cells (MCF-7/ADR), resulting in increased the chemotherapy efficacy. In addition, the total number of side population cells that exhibit the properties of cancer stem-like cells were also reduced by the combination of photodynamic therapy and chemotherapy. In conclusion, DOX-NPs/Ce6-MBs will provide a platform for simultaneously overcoming MDR and increasing drug delivery and therefore, treatment efficiency, under ultrasound irradiation.

Self-assemble tannic acid and iron complexes on pure nanodrugs surface prevents aggregation and enhances anticancer drug delivery efficiency

The development of pure nanodrugs (PNDs) has led to the possibility of delivering the anticancer agents without involving nanocarriers. On the path to its clinical application, the dispersion stability of PNDs must be improved. In the present study, we tried to improve the dispersion stability of ester-linked SN-38 dimer by surface modification with coordination complexes between tannic acid (TA) and metal ions. TA and FeIII complexes coated SN-38 dimer PNDs (TA-Fe/PNDs) showed superior colloidal stability as they did not show aggregation, comparing to non-coated PNDs. It was also found that the release of the active SN-38 moiety from TA-Fe/PNDs was faster than that from the aggregated PNDs, because of the larger surface area in contact with the enzyme of mouse serum to facilitate the drug release.

Cationic cellulose nanocrystals complexed with polymeric siRNA for efficient anticancer drug delivery

Surface-modified cellulose nanocrystals (CNCs) were developed for efficient delivery of polymeric siRNA in cancer cells. Cationic CNCs were synthesized using the sequential process of hydrothermal desulfation and chemical modification following which, polymeric siRNA obtained using from a two-step process of rolling circle transcription and Mg2+ chelation was complexed with the modified CNCs by electrostatic interaction. The complexation efficiency was optimized for high drug loading and release in the cytoplasmic environment. The resultant nanocomplex showed significantly enhanced enzymatic stability, gene knockdown efficacy, and apoptosis-induced in vitro therapeutic effect. Our results suggest CNCs as a promising carbohydrate-based delivery platform which could be utilized for RNAi-mediated cancer therapeutics.

Photo-responsive degradable hollow mesoporous organosilica nanoplatforms for drug delivery

BackgroundStimulus-responsive degradable mesoporous organosilica nanoparticles (MONs) have shown great promise as drug carriers via enhancing the efficiency of drug delivery and accelerating the degradation of nanocarriers. However, it remains a great challenge to develop novel light-enabled spatial and temporal degradable MONs with both superior responsiveness for efficient anti-cancer drug delivery and safe exocytosis.ResultsWe report a novel photo-responsive degradable hollow mesoporous organosilica nanoplatform (HMONs@GOQD). The platform is based on organosilica nanoparticles (HMONs) containing singlet oxygen (1O2)-responsive bridged organoalkoxysilanes and wrapped graphene oxide quantum dots (GOQDs). The unique hollow mesoporous structure of the HMONs guarantees an excellent drug loading and release profile. During light irradiation, 1O2 produced by the GOQDs leads to the degradation of the organosilica nanoparticles, resulting in enhanced local drug release.ConclusionsWe carried out in vitro and in vivo experiments using DOX as a model drug; DOX-HMONs@GOQDs exhibited high biocompatibility, accelerated degradation, and superior therapeutic efficacy during light irradiation, indicating a promising platform for clinical cancer therapy.

Effects of the molecular weight and molar ratio of poly(2-ethyl-2-oxazoline)-based lipid on the pH sensitivity, stability, and antitumor efficacy of liposomes

In this study, we evaluated and screened the effects of the molecular weight (MW) and molar ratio of poly(2-ethyl-2-oxazoline)-cholesteryl methyl carbonate (PEtOz-CHMC) on the pH sensitivity, stability, and antitumor efficacy of liposomes. The pH sensitivity of PEtOz-CHMC with different MWs and molar ratios was screened by drug release and cytotoxicity experiments at different pH levels. Results indicated that the liposomes coated with PEtOz1k-CHMC (7% molar ratio) and PEtOz2k-CHMC (5% molar ratio) exhibited the desirable pH responsiveness. When the MW of PEtOz was relatively low, 7% of the modified ratio obtained the strongest stability, but the turbidity of the liposomes did not obviously change when the molar ratio of PEtOz-CHMC was further increased. A375 cells were used as models to investigate the cellular uptake and intracellular localization of coumarin-6-loaded liposomes (C6-L), PEGylated liposomes (PEG-C6-L), and PEtOzylated liposomes. PEtOz1k-C6-L and PEtOz2k-C6-L presented remarkably stronger fluorescence intensity at low pH than at pH 7.4, whereas C6-L and PEG-C6-L did not achieve any obvious diversity at different pH conditions. Compared with C6-L and PEG-C6-L, PEtOz-C6-L showed efficient intracellular trafficking, including endosomal/lysosomal escape and cytoplasmic release. Pharmacokinetic experiments demonstrated that half-lives of PEG2k-C6-L, PEtOz2k-C6-L, and PEtOz1k-C6-L were 11.89-, 7.00-, and 5.29-fold times higher than those of C6-L, respectively. Among the liposomes, the DOX·HCl-loaded liposomes coated with PEtOz2k-CHMC demonstrated the strongest antitumor efficacy against B16 tumor xenograft models in vivo. These findings provide the feasibility of using PEtOz-CHMC with optimal pH sensitivity and long circulation to extend the application of liposomes to efficient anticancer drug delivery.

Electrospray-based synthesis of fluorescent poly(d,l-lactide-co-glycolide) nanoparticles for the efficient delivery of an anticancer drug and self-monitoring its effect in drug-resistant breast cancer cells

A novel approach used to synthesize antimetabolite-conjugated and intense blue fluorescence-emitting smart polymeric nanoparticles is reported for the efficient delivery of anticancer drugs and self-monitoring their effect in drug-resistant metastatic breast cancer cells.

FRET-based intracellular investigation of nanoprodrugs toward highly efficient anticancer drug delivery.

In order to overcome unpredictable side-effects and increased cytotoxicity of conventional carrier-based anticancer drug delivery systems, several systems that consist exclusively of the pure drug (or prodrug) have been proposed. The behavior and dynamics of these systems after entering cancer cells are, however, still unknown, hindering their progress towards in vivo and clinical applications. Here, we report a comprehensive in cellulo study of carrier-free SN-38 nanoprodrugs (NPDs), previously developed by our group. The work shows the intracellular uptake, localization, and degradation of the NPDs via FRET microscopy. Accordingly, new FRET-NPDs were chemically synthesized and characterized. Prodrug to drug conversion and therapeutic efficiency were also validated. Our work provides crucial information for the application of NPDs as drug delivery systems and demonstrates their outstanding potential as next-generation anticancer nanomedicines.

Tailor-made legumain/pH dual-responsive doxorubicin prodrug-embedded nanoparticles for efficient anticancer drug delivery and in situ monitoring of drug release.

Legumain enzyme is a well-conserved lysosomal cysteine protease and is over-expressed in many tumor cells and tumor stromal cells and exhibits higher protease activity under acidic conditions, such as in lysosomes and endosomes. Legumain enzyme-triggered drug delivery systems have demonstrated potential therapeutic values in cancer targeted therapy. To realize a more efficient delivery of anticancer therapeutic agents, we herein report a legumain/pH dual-responsive drug delivery system for enhancing site-specific controlled release of antitumor drugs. The carrier (named "DS-NA") is a hybrid vector constituting PEG-b-PBLA polymers, pH-responsive OAPI polymers, and legumain-sensitive peptide-doxorubicin prodrug decorated fluorescent carbon dots (CDs-C9-AANL-DOX). In tumor cells, DS-NA could disassemble rapidly in acidic environments, and then release doxorubicin through legumain digestion. Except as a drug vector, the drug release process from DS-NA could also be dynamically monitored by CLSM as the DOX was released from the surface of CDs through the AANL peptide linker digested by legumain, then transferred into the cell nucleus and exerted cytotoxicity, while the CDs themselves remained in the cytoplasm. As a control, the CDs-C9-DOX, which did not contain the AANL peptide linker, also still resided in the cytoplasm. Furthermore, in vivo studies show that DS-NA had a stronger inhibitory effect on tumor tissue with attenuated side effects to normal tissues than control nanoparticles or free drugs, which may be due to comprehensive effects including pH/legumain dual-triggered drug release, long blood circulation periods, and EPR effects. Together, a combination strategy of acid sensitivity and legumain enzyme sensitivity used for site-specific controlled release of drugs provides a novel method for enhanced and precise antitumor chemotherapy.

Actively Targeted and Redox Responsive Delivery of Anticancer Drug by Chitosan Nanoparticles.

The clinical efficacy of methotrexate (MTX) is limited by its poor water solubility, its low bioavailability, and the development of resistance in cancer cells. Herein, we developed novel folate redox-responsive chitosan (FTC) nanoparticles for intracellular MTX delivery. l-Cysteine and folic acid molecules were selected to be covalently linked to chitosan in order to confer it redox responsiveness and active targeting of folate receptors (FRs). NPs based on these novel polymers could possess tumor specificity and a controlled drug release due to the overexpression of FRs and high concentration of reductive agents in the microenvironment of cancer cells. Nanoparticles (NPs) were prepared using an ionotropic gelation technique and characterized in terms of size, morphology, and loading capacity. In vitro drug release profiles exhibited a glutathione (GSH) dependence. In the normal physiological environment, NPs maintained good stability, whereas, in a reducing environment similar to tumor cells, the encapsulated MTX was promptly released. The anticancer activity of MTX-loaded FTC-NPs was also studied by incubating HeLa cells with formulations for various time and concentration intervals. A significant reduction in viability was observed in a dose- and time-dependent manner. In particular, FTC-NPs showed a better inhibition effect on HeLa cancer cell proliferation compared to non-target chitosan-based NPs used as control. The selective cellular uptake of FTC-NPs via FRs was evaluated and confirmed by fluorescence microscopy. Overall, the designed NPs provide an attractive strategy and potential platform for efficient intracellular anticancer drug delivery.

Developments in Platinum-Group Metals as Dual Antibacterial and Anticancer Agents

Platinum-group (PG) complexes have been used as antibacterial and anticancer agents since the discovery of cisplatin. The science world still requires improvement on these complexes because of multidrug and antineoplastic resistances. This review observes discoverers and history of these platinum-group metals (PGMs), as well as their beneficial applications. The focus of this study was biological applications of PGMs in relation to human health. Sandwich and half-sandwich PGM coordination compounds and their metal nanoparticles give improved results for biological activities by enhancing efficient delivery of both antibacterial and anticancer drugs, as well as luminescent bioimaging (biomarkers) for biological identifications.

Efficient Intestinal Digestion and On Site Tumor-Bioactivation are the Two Important Determinants for Chylomicron-Mediated Lymph-Targeting Triglyceride-Mimetic Docetaxel Oral Prodrugs.

The oral absorption of chemotherapeutical drugs is restricted by poor solubility and permeability, high first‐pass metabolism, and gastrointestinal toxicity. Intestinal lymphatic transport of lipophilic prodrugs is a promising strategy to improve the oral delivery efficiency of anticancer drugs via entrapment into a lipid formulation and to avoid first‐pass metabolism. However, several basic principles have still not been clarified, such as intestinal digestibility and stability and on‐site tumor bioactivation. Herein, triglyceride‐mimetic prodrugs of docetaxel (DTX) are designed by conjugating them to the sn‐2 position of triglyceride (TG) through different linkage bonds. The role of intestinal digestion in oral absorption of TG‐like prodrugs is then investigated by introducing significant steric‐hindrance α‐substituents into the prodrugs. It is surprisingly found that poor intestinal digestion leads to an unsatisfactory bioavailability but efficient intestinal digestion of TG‐like prodrugs with a less steric‐hindrance linkage (DTX‐S‐S‐TG) facilitating oral absorption. Moreover, it is found that the TG‐like reduction‐sensitive prodrug (DTX‐S‐S‐TG) has good stability during intestinal transport and blood circulation, and on‐demand release of docetaxel at the tumor site, leading to a significantly improved antitumor efficiency with negligible gastrointestinal toxicity. In summary, the chylomicron‐mediated lymph‐targeting triglyceride‐mimetic oral prodrug approach provides a good foundation for the development of oral chemotherapeutical formulations.

Novel pH-responsive biodegradable organosilica nanoparticles as drug delivery system for cancer therapy

Although the biodegradability of silica has been verified, the complete and safe excretion of mesoporous silica nanoparticles (MSNs) from the biological system still impede their clinical translation. Herein, novel pH-responsive biodegradable hollow mesoporous organosilica nanoparticles (PBHMONs) based on pH-responsive silsesquioxane were successfully prepared for efficient anti-cancer drug delivery. pH-responsive cleavable bridges containing acetal moieties were prepared and then inserted directly into the framework of the MONs and the hollow nanostructures were achieved by silica-etching chemistry (alkaline etching). PBHMONs exhibited particularly high drug loading capacities for drugs (DOX) owing to the hollow mesoporous structure, and a uniquely low premature leakage owing to π-π interactions. Moreover, the pH-responsive biodegradation of the PBHMONs in the weakly acidic microenvironment of tumor cells led to partial drug release, as well as potential enabling rapid excretion and preventing long-term retention/toxicity.

Multifunctional Fe3O4@C-based nanoparticles coupling optical/MRI imaging and pH/photothermal controllable drug release as efficient anti-cancer drug delivery platforms

Multifunctional nanomedicines featuring high drug loading capacity, controllable drug release and real-time self-monitoring are attracting increasing attention due to their potential to improve cancer therapeutic efficacy. Herein, a new kind of Fe3O4@C-based nanoparticles modified with isoreticular metal organic frameworks (IRMOF-3), folic acid (FA) and detachable polyethylene glycol (PEG) under tumor microenvironment was developed. The core-shell structured Fe3O4@C was synthesized via the one-pot solvothermal reaction and the IRMOF-3 layers were coated on the outer shell of Fe3O4@C through layer-by-layer coating method. The FA and PEG were conjugated on the surface of nanoparticles by reacting with the amine groups provided by IRMOF-3. The as-synthesized nanoparticles showed stable photothermal effect, superparamagnetic properties and blue fluorescence characteristic under 360 nm irradiation. The in vitro experiments showed that the drug loaded nanoparticles exhibit pH-dependent drug release property, and PEGylation was proved effective in suppressing burst drug release (only 8.0% of drugs were released within 95 h). The confocal laser scanning microscopy study revealed that the as-synthesized nanoparticles could serve as a cell imaging agent and the cell internalization can be significantly enhanced after FA modified. The IRMOF-3 modified nanoparticles showed negligible cytotoxicity and the drug loaded nanoparticles showed pH/photothermal-stimuli enhanced cytotoxicity in vitro. It is believed that the present smart drug delivery platforms will hold great potential in imaging guided drug delivery and cancer therapy.

Multistage pH-responsive mesoporous silica nanohybrids with charge reversal and intracellular release for efficient anticancer drug delivery

This study introduced multistage pH-responsive nanohybrids (MSN-hyd-MOP) based on mesoporous silica nanoparticles (MSNs) modified with polymers with charge-reversal property via an acid-labile hydrazone linker, which were applied as a drug delivery system loaded anticancer drugs. In this study, MSN-hyd-MOP nanohybrids were completely investigated for their synthesis, pH response, drug release behavior, cytotoxicity capability and endocytic behavior. Responding to the acidic extracellular microenvironment of solid tumor (pH 6.5), MSN-hyd-MOP nanohybrids exhibited surface charge-reversal characteristic from negative (−10.2 mV, pH 7.4) to positive (16.6 mV, pH 6.5). The model drug doxorubicin (Dox) was efficiently loaded within the channels of MSN-hyd-MOP (encapsulation efficiency about 87%). The increased acidity in endo-/lysosome promote Dox-loaded MSN-hyd-MOP (MSN-hyd-MOP@Dox) release Dox quickly. In vitro study revealed the drug delivery system had good biocompatibility and could deliver the payload to tumor cells. Overall, the described nanohybrids can be used as a potential anticancer drug delivery system.

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

Enhancing tumor targeting of nanocarriers has been a major strategy for advancing clinical translation of cancer nanomedicines. Herein, we report a head-to-head comparison between 5 nm renal clearable and 30 nm non-renal clearable gold nanoparticle (AuNP)-based drug delivery systems (DDSs) in the delivery of doxorubicin (DOX). While the two DDSs themselves had comparable tumor targeting, we found their different vascular permeability played an even more important role than blood retention in the delivery and intratumoral transport of DOX, of which tumor accumulation, efficacy, and therapeutic index were enhanced 2, 7, and 10-fold, respectively, for the 5 nm DDS over 30 nm one. These findings indicate that ultrahigh vascular permeability of renal clearable nanocarriers can be utilized to further improve anticancer drug delivery without the need for prolonged blood retention.

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

AbstractEnhancing tumor targeting of nanocarriers has been a major strategy for advancing clinical translation of cancer nanomedicines. Herein, we report a head‐to‐head comparison between 5 nm renal clearable and 30 nm non‐renal clearable gold nanoparticle (AuNP)‐based drug delivery systems (DDSs) in the delivery of doxorubicin (DOX). While the two DDSs themselves had comparable tumor targeting, we found their different vascular permeability played an even more important role than blood retention in the delivery and intratumoral transport of DOX, of which tumor accumulation, efficacy, and therapeutic index were enhanced 2, 7, and 10‐fold, respectively, for the 5 nm DDS over 30 nm one. These findings indicate that ultrahigh vascular permeability of renal clearable nanocarriers can be utilized to further improve anticancer drug delivery without the need for prolonged blood retention.