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Cited by 1,066Nanoparticle-Based Drug DeliveryAdvanced Drug Delivery SystemsRNA Interference and Gene Delivery

The Smart Drug Delivery System and Its Clinical Potential

Open access
Liu, Dong, Yang, Fang, Xiong, Fei, Gu, Ning·2016·Theranostics
DOI 10.7150/thno.14858PMC PMC4924501
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Abstract

With the unprecedented progresses of biomedical nanotechnology during the past few decades, conventional drug delivery systems (DDSs) have been involved into smart DDSs with stimuli-responsive characteristics. Benefiting from the response to specific internal or external triggers, those well-defined nanoplatforms can increase the drug targeting efficacy, in the meantime, reduce side effects/toxicities of payloads, which are key factors for improving patient compliance. In academic field, variety of smart DDSs have been abundantly demonstrated for various intriguing systems, such as stimuli-responsive polymeric nanoparticles, liposomes, metals/metal oxides, and exosomes. However, these nanoplatforms are lack of standardized manufacturing method, toxicity assessment experience, and clear relevance between the pre-clinical and clinical studies, resulting in the huge difficulties to obtain regulatory and ethics approval. Therefore, such relatively complex stimulus-sensitive nano-DDSs are not currently approved for clinical use. In this review, we highlight the recent advances of smart nanoplatforms for targeting drug delivery. Furthermore, the clinical translation obstacles faced by these smart nanoplatforms have been reviewed and discussed. We also present the future directions and perspectives of stimuli-sensitive DDS in clinical applications.

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes stimuli-responsive “smart” drug delivery nanoplatforms—polymeric nanoparticles, liposomes, organic-inorganic hybrids, and exosomes—and their clinical translation barriers. It argues that although such systems can improve targeting and reduce side effects, most remain unapproved because of manufacturing, safety, reproducibility, regulatory, and preclinical-to-clinical relevance challenges.

Key findings

  • Smart DDSs are designed to release payloads only at target sites in response to endogenous triggers (pH, redox, enzymes, glucose, small biomolecules) or exogenous triggers (temperature, magnetic field, ultrasound, light, electric pulse/high-energy radiation).
  • pH and redox gradients provide quantitative targeting rationales: tumor extracellular pH is usually below 7.0 versus about 7.4 in normal tissue/blood; endosomal/lysosomal pH ranges from 4.5 to 5.5. GSH is 2–20 μM in blood/normal extracellular matrices versus 2–10 mM in cancer cells (100- to 500-fold higher), and mucosal ROS in inflammatory tissues and colon cancer is 10- to 100-fold higher than normal tissues.
  • Thermo-sensitive nanocarriers are typically designed to retain payloads around 37°C and release rapidly above 40–45°C; ThermoDox uses DPPC’s 41.5°C melting temperature, showed improved safety versus free doxorubicin in a Phase I trial, but its Phase III results failed to reach the 33% life-span threshold.
  • Clinically, Doxil, Lipusu, and Abraxane are approved nanomedicines, but Visudyne is described as the only FDA-approved nanomedicine with a stimuli-responsive nanoplatform concept; other stimuli-responsive DDSs remain at clinical stage. Obstacles include scale-up, batch-to-batch reproducibility, safety/toxicity assessment, regulatory frameworks, and poor predictive value of small-animal models.

Methods

  • Narrative review of smart drug delivery systems, focusing on stimuli-responsive polymeric nanoparticles, liposomes, organic-inorganic hybrid nanoparticles, and exosomes.
  • Synthesizes prior literature and selected examples rather than presenting primary experimental data, patient samples, or a systematic search strategy.
  • Discusses design rationales for endogenous/exogenous triggers and reviews clinical translation obstacles, including manufacturing, safety, regulation, and animal-to-human relevance.

Limitations

  • The paper states that smart nanoplatforms lack standardized manufacturing methods, toxicity assessment experience, and clear relevance between preclinical and clinical studies, causing regulatory and ethics approval difficulties; such stimulus-sensitive nano-DDSs are not currently approved for clinical use.
  • It states that endogenous triggers vary greatly between patients, while exogenous triggers face normal tissue damage and tissue-penetration depth problems; animal models often fail to reproduce human disease because of inbreeding, and there are limited publications on orally administered nanoscale DDSs.
  • Evident from the text: this is a narrative review with no systematic search, inclusion criteria, meta-analysis, or primary data, so examples and conclusions are selective rather than exhaustive.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.7150/thno.14858

Cites

176 of 176 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 37 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Mucosal ROS concentrations in inflammatory tissues and colon cancer are 10- to 100-fold higher than in normal tissues.

    “It has been reported the mucosal ROS concentrations in inflammatory tissues and colon cancer were 10- to 100- fold higher than that of normal tissues 19, 35.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [19] Mura S Nicolas J Couvreur P Stimuli-responsive nanocarriers for drug delivery Nature Materials 2013 12 991 1003 24150417

      Not checked in the free run.

    • cites [35] Wilson DS Dalmasso G Wang L Sitaraman SV Merlin D Murthy N Orally delivered thioketal nanoparticles loaded with TNF-α-siRNA target inflammation and inhibit gene expression in the intestines Nature Materials 2010 9 923 8 20935658 PMC3142359

      Not checked in the free run.

  • Premisecitation

    Ultrasonic sensitive nanocarriers expand US techniques to capture drug carriers and trigger drug release at desired sites by tuning US frequency, duty cycles, and time of exposure.

    “The development of ultrasonic sensitive nanocarriers for ultrasonography expands US techniques to be a unique and effective method to capture drug carriers and trigger drug release at the desired sites by tuning the US frequency, duty cycles and time of exposure 61.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [61] Paris JL Cabañas MV Manzano M Vallet-Regí M Polymer-Grafted Mesoporous Silica Nanoparticles as Ultrasound-Responsive Drug Carriers ACS Nano 2015 9 11023 33 26456489

      Not checked in the free run.

  • Premisecitation

    Few nanomaterial-based smart drug carriers have been translated into clinics for real-world applications.

    “Although recent research and reviews have developed and summarized several novel aspects for nanomaterials that being used as smart drug carriers 1-6, few of them have been finally translated into clinics for real-world applications 7-9.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [7] Alvarez-Lorenzo C Concheiro A Smart drug delivery systems: from fundamentals to the clinic Chemical Communications 2014 50 7743 65 24805962

      Not checked in the free run.

    • cites [8] Crommelin DJ Florence AT Towards more effective advanced drug delivery systems International Journal of Pharmaceutics 2013 454 496 511 23415662

      Not checked in the free run.

    • cites [9] Holzapfel BM Reichert JC Schantz J-T Gbureck U Rackwitz L Nöth U How smart do biomaterials need to be? A translational science and clinical point of view Advanced Drug Delivery Reviews 2013 65 581 603 22820527

      Not checked in the free run.

  • Premisecitation

    GSH levels within cancer cells range from 2 to 10 mM, which is 100- to 500-fold higher than normal ranges.

    “On one hand, concentrations of GSH in blood and normal extracellular matrices are reported to be 2-20 μM, at the same time GSH levels within cancer cell ranges from 2 to 10 mM, which is 100- to 500- fold higher than the normal ranges 34.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Torchilin VP Multifunctional, stimuli-sensitive nanoparticulate systems for drug delivery Nature Reviews Drug Discovery 2014 13 813 27 25287120 PMC4489143

      Not checked in the free run.

  • Premisecitation

    Mean extracellular pH values in various solid tumors are usually below 7.0.

    “However, because of high rate of glycolysis, the mean extracellular pH values in various solid tumors are usually below 7.0 27, 28.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [27] Neri D Supuran CT Interfering with pH regulation in tumours as a therapeutic strategy Nature Reviews Drug Discovery 2011 10 767 77 21921921

      Not checked in the free run.

    • cites [28] Lee ES Oh KT Kim D Youn YS Bae YH Tumor pH-responsive flower-like micelles of poly (L-lactic acid)-b-poly (ethylene glycol)-b-poly (L-histidine) Journal of Controlled Release 2007 123 19 26 17826863 PMC2196406

      Not checked in the free run.

  • May combine two claims. 19
  • Classified as probably not a substantial claim. 14

  • May combine two claims.

    Interpretationnone given

    Stimulus-sensitive nanoplatforms lack standardized manufacturing methods, toxicity assessment experience, and clear relevance between pre-clinical and clinical studies, causing difficulties in obtaining regulatory and ethics approval.

    “However, these nanoplatforms are lack of standardized manufacturing method, toxicity assessment experience, and clear relevance between the pre-clinical and clinical studies, resulting in the huge difficulties to obtain regulatory and ethics approval.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Smart drug delivery systems with stimuli-responsive characteristics can increase drug targeting efficacy and reduce side effects/toxicities of payloads.

    “Benefiting from the response to specific internal or external triggers, those well-defined nanoplatforms can increase the drug targeting efficacy, in the meantime, reduce side effects/toxicities of payloads, which are key factors for improving patient compliance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A pH-sensitive DDS enabled fast release of disulfiram, inhibited P-glycoprotein activity, and rehabilitated apoptotic signaling pathways, while doxorubicin conjugated by hydrazone bond was released with a pH-dependent process.

    “The system was designed to treat multidrug resistance (MDR) cancer, and the result showed that the pH-sensitive DDS enabled a fast release of DSF. It could inhibit the activity of P-glycoprotein (P-gp) and rehabilitate the signaling pathways of cell apoptotic, while DOX conjugated by hydrazone bond was released with pH-dependent process.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [85] Duan X Xiao J Yin Q Zhang Z Yu H Mao S Smart pH-sensitive and temporal-controlled polymeric micelles for effective combination therapy of doxorubicin and disulfiram ACS Nano 2013 7 5858 69 23734880

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    All these issues challenge clinical applications of stimulus-sensitive DDSs and must be solved to ensure successful clinical translation.

    “In summary, all these issues challenge the clinical applications of stimulus-sensitive DDSs. These issues for smart DDSs must be solved to ensure the successful clinical translation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationnone given

    Main challenges for current exosome research are data collection and classification, and establishment of related evaluation and test methods, which are key issues for clinical application.

    “Moreover, main challenges for current research on exosomes are data collection and classification, as well as the establishment of related evaluation and test methods, which are key issues need to be addressed for clinical application.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The FDA guidance released in 2014 is the only official regulation that can be referenced for the nanomedicine industry; despite defining the scope of nanomaterials, it is far from sufficient for the nano-pharmaceutical industry.

    “The guidance be named “Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology” was released by FDA in 2014, which is the only official regulation that can be referenced for nanomedicine industry. Despite the scope of nanomaterials are defined in the guidance, which is far from sufficient for nano-pharmaceutical industry 192.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [192] Wicki A Witzigmann D Balasubramanian V Huwyler J Nanomedicine in cancer therapy: challenges, opportunities, and clinical applications Journal of Controlled Release 2015 200 138 57 25545217

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Surface modification with organic functional groups may solve AuNP non-biodegradability and accumulation.

    “Such problem may be solved by surface modification of the organic functional groups.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: AuNPs are not biodegradable and gradually accumulate in the body after systemic administration.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given

    It will be an enormous challenge for researchers to improve preclinical research of advanced DDSs to reproducible and translatable production to clinical-trial success.

    “It will be an enormous challenge for researchers to improve preclinical research of advanced DDSs to reproducible and translatable production to clinical-trial success.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Doxil is the first FDA-approved nanomedicine delivery system and is based on PEGylated liposomes.

    “Doxil®, the first Food and Drug Administration (FDA) approved nanomedicine delivery system is based on PEGylated liposomes 115.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [115] Barenholz YC Doxil®—the first FDA-approved nano-drug: lessons learned Journal of Controlled Release 2012 160 117 34 22484195

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Compared with conventional DDS, stimuli-responsive DDSs may be more prone to inter-subject variability in performance, raising issues with reproducibility in safety and efficacy.

    “Moreover, compared with conventional DDS, stimuli-responsive DDSs maybe more prone to inter-subject variability in their performance, thus raising issues with reproducibility in safety/ efficacy.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Safety issues and toxicity are still priority needs to be fulfilled by smart DDSs.

    “The safety issues as well as toxicity are still priority needs to be fulfilled by the smart DDSs.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationnone given

    Hybrid smart nano-DDS in an all-in-one strategy still has aspects to be improved, including intrinsic low sensitivity, high cost of manufacture, toxicity, and non-biodegradable nature; the current developmental stage of theranostic hybrid smart DDSs is still early.

    “Despite of its the fast progress, the hybrid smart nano-DDS in all-in-one strategy still has some aspects to be improved, such as the intrinsic low sensitivity, high cost of manufacture, toxicity and non-biodegradable nature. The current developmental stage of theranostic hybrid smart DDSs are still in their early stage.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    The application of exosomes as DDS has not been largely explored and many challenges remain; one major challenge is maintaining their biological properties during the therapeutics loading process.

    “However, as an emerging area, the application of exosomes as DDS has not been largely explored and there are still many challenges ahead. One of the major challenges is to maintain their biological properties during the therapeutics loading process.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Exosomes are ideal drug delivery vehicles because they can load specific drugs for personalized medicine, show different biological effects and targeting specificities from various host cells, and are well biocompatible with the lowest cytotoxicity.

    “Many features suggest that the exosomes are ideal drug delivery vehicles. Firstly, exosomes can load with specific drugs to serve as carriers for personalized medicine. Since exosomes released from various types of host cells, they show different biological effects and targeting specificities. Secondly, exosomes are well biocompatible with the lowest cytotoxicity.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationnone given

    Although MSNPs as organic-inorganic hybrid smart DDS show superior biocompatibility, their pharmacokinetics and pharmacodynamics should be further evaluated.

    “Compared with other inorganic nanoparticles, although MSNPs served as organic-inorganic hybrid smart DDS and shows superior biocompatibility, the pharmacokinetics and pharmacodynamics of MSNPs should be further evaluated.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Although smart nano-DDSs have shown to be much more efficient in both diagnosis and therapy, potential druggability still needs to be evaluated before smart DDSs reach clinics.

    “Although smart nano-DDSs have shown to be much more efficient in both diagnosis and therapy, potential druggability still needs to be evaluated before the smart DDSs reach to clinics.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Ultra pH-sensitive fluorescent nanoprobes were silent during blood circulation and strongly activated (>300-fold) in response to acidic extracellular pH in tumors or neovasculature.

    “These nanoprobes were silent during the blood circulation, while strongly activated (>300-fold) in response to the acidic extracellular pH in tumors or in the neovasculature.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [94] Zhou K Wang Y Huang X Luby-Phelps K Sumer BD Gao J Tunable, Ultrasensitive pH-Responsive Nanoparticles Targeting Specific Endocytic Organelles in Living Cells Angewandte Chemie International Edition 2011 50 6109 14 PMC3438661 21495146

      Not checked in the free run.

    • cites [95] Wang Y Zhou K Huang G Hensley C Huang X Ma X A nanoparticle-based strategy for the imaging of a broad range of tumours by nonlinear amplification of microenvironment signals Nature Materials 2014 13 204 12 24317187 PMC3946908

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Interpretationnone given

    For advanced DDSs, it is reasonable to develop effective evaluation strategies for toxicology, pharmacokinetics, and pharmacodynamics based on animal models.

    “Last but not the least, for the advanced DDSs, it is reasonable to develop the effective evaluation strategies for a good appreciation of toxicology, pharmacokinetics and pharmacodynamics based on animal models.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Orally administered thioketal nanoparticles loaded with siRNA could diminish TNF-messenger RNA levels in the colon and protected mice from ulcerative colitis.

    “It has been demonstrated that orally administered TKNs loaded with siRNA could diminish TNF-messenger RNA levels in the colon and protected mice from ulcerative colitis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] Wilson DS Dalmasso G Wang L Sitaraman SV Merlin D Murthy N Orally delivered thioketal nanoparticles loaded with TNF-α-siRNA target inflammation and inhibit gene expression in the intestines Nature Materials 2010 9 923 8 20935658 PMC3142359

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Mouse models of various diseases need to fully consider their complexity by bringing population diversity into disease modelling rather than relying on inbred strains of laboratory animals.

    “Accordingly, mouse models of various diseases need fully consider their complexity by bringing in population diversity into disease modelling rather than relying on inbred strains of laboratory animals 194, 195.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [194] Hunter KW Mouse models of cancer: does the strain matter? Nature Reviews Cancer 2012 12 144 9 PMC6309955 22257951

      Not checked in the free run.

    • cites [195] Teicher BA Tumor models for efficacy determination Molecular Cancer Therapeutics 2006 5 2435 43 17041086

      Not checked in the free run.

    • Rests on an assumption: Current animal models fail to accurately reproduce human diseases because of inbreeding.
    • Rests on an assumption: Each human being is unique, creating diversity and complexity of disease.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationnone given

    There are limited publications of safety, pharmacokinetic, and pharmacodynamic studies on orally administrated nanoscale DDSs, and current research is much more focused on smart rather than basics.

    “Unfortunately, there are limited publications of such studies on the orally administrated nanoscale DDSs, and current research is much more focused on “smart” instead of “basics”.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationnone given

    An extremely large number of optimization and improvement experiments are needed for translation of each stimulus from preclinical experimental models to routine clinical practice.

    “Besides, an extremely large numbers of optimizations and improvements experiments are needed for the translation of each stimulus from preclinical experimental models to routine clinical practice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Though a number of nanomedicines have been approved by the FDA and EMA, frameworks for regulation of nano-enabled medical products acceptable for pharmaceutical and medical-device companies and the public are not available yet.

    “Though a number of nanomedicines have been approved by the FDA and European Medicines Agency (EMA), frameworks for the regulation of nano-enabled medical products acceptable for pharmaceutical and medical-device companies and public are not available yet 191.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [191] Helmus MN The need for rules and regulations Nature Nanotechnology 2007 2 333 4 18654297

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Although NCI and FDA have done work on standardization of nanomedicine characterizations and analyses, there is still a long way to create standardized definitions and protocols to characterize nanomedicines for clinics.

    “Although the National Cancer Institute (NCI) and FDA have done a lot of work on standardization of nanomedicine characterizations and analyses, there are still a long way to create standardized definitions and protocols to characterize nanomedicines for clinics.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Exogenous stimuli responsive systems are easier to control and more promising for clinic, but major improvements are required to solve normal tissue damage and tissue-penetration depth.

    “Although exogenous stimuli responsive systems are much easier to be controlled and is much more promising for clinic, major improvements would be required to solve problems related to normal tissue damage and tissue-penetration depth 19.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Mura S Nicolas J Couvreur P Stimuli-responsive nanocarriers for drug delivery Nature Materials 2013 12 991 1003 24150417

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Major issues for clinical translation of nanomedicine include industrial scale-up validation, batch-to-batch reproducibility, and controllability of nanomaterials' physicochemical properties.

    “Thirdly, major issues for clinical translation of nanomedicine include industrial scale-up validation, batch-to-batch reproducibility, as well as controllability of nanomaterials' physicochemical properties.”
    Quote in the paperSubstantial claim
26 of 26

  • The paper relies on this without support.

    Conventional drug delivery systems are often accompanied by systemic side effects mainly attributable to nonspecific bio-distribution and uncontrollable drug release characteristics.

    “Conventional drug delivery systems (DDSs) are often accompanied by systemic side effects that mainly attributable to their nonspecific bio-distribution and uncontrollable drug release characteristics.”

  • The paper relies on this without support.

    Smart controlled DDSs can effectively reduce dosage frequency while maintaining drug concentration in targeted organs/tissues for a longer period.

    “In comparison to the conventional DDSs, the smart controlled DDSs can effectively reduce the dosage frequency, while maintaining the drug concentration in targeted organs/tissues for a longer period of time.”

  • The paper relies on this without support.

    Current treatment of diabetics to control blood glucose levels by long-term oral administration or daily insulin injections results in poor patient compliance.

    “The current treatment of diabetics to control blood glucose levels is normally realized by long-term perioral administration or daily insulin injections, which results in a poor compliance to the patients.”

  • The paper relies on this without support.

    Intracellular GSH can trigger the exchange of thiol-disulfide bonds.

    “It is well noted that intracellular GSH can trigger the exchange of thiol-disulfide bond.”

  • The paper relies on this without support.

    MSNPs possess a large loading capacity, but loaded drugs are always easily released immediately after administration.

    “Although mesoporous silica nanoparticles (MSNPs) possess a large loading capacity, the loaded drugs are always easily released immediately after administration.”

  • The paper relies on this without support.

    AuNPs are not biodegradable and gradually accumulate in the body after systemic administration.

    “However, as inorganic nanomaterials, AuNPs are not biodegradable and gradually accumulate in the body after systemic administration.”

  • The paper relies on this without support.

    Current animal models fail to accurately reproduce human diseases because of inbreeding.

    “Nevertheless, current animal models fail to accurately reproduce human diseases because of inbreeding.”

  • The paper relies on this without support.

    Each human being is unique, creating diversity and complexity of disease.

    “Each human being is unique, therefore, the diversity and complexity of the disease have been created.”
8 of 8

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Diseased/tumor tissues have the physiological characteristics of higher temperature (40-42 °C) than normal tissues (37 °C).

    “Since diseased/tumor tissues have the physiological characteristics of higher temperature (40–42 °C) than normal tissues (37 °C).169”

    From Smart nanoparticles for cancer therapy (2023) · cites this paper as [169]

Cites

Flagged first, then by citations

Research works printed but not linked: 7

  1. [1]Hrubý M Filippov SK Štěpánek P Smart polymers in drug delivery systems on crossroads: Which way deserves following? European Polymer Journal 2015 65 82 97
  2. [17]Tanaka T Collapse of gels and the critical endpoint Physical Review Letters 1978 40 820
  3. [48]Liu J Zhang Y Wang C Xu R Chen Z Gu N Magnetically sensitive alginate-templated polyelectrolyte multilayer microcapsules for controlled release of doxorubicin The Journal of Physical Chemistry C 2010 114 7673 9
  4. [66]Yun J Im JS Lee Y-S Kim H-I Electro-responsive transdermal drug delivery behavior of PVA/PAA/MWCNT nanofibers European Polymer Journal 2011 47 1893 902
  5. [100]Wang W Lin J Cai C Lin S Optical properties of amphiphilic copolymer-based self-assemblies European Polymer Journal 2015 65 112 31
  6. [114]Torchilin V Liposomes in drug delivery Fundamentals and Applications of Controlled Release Drug Delivery Springer 2012 p289-328
  7. [144]Sanchez C Julián B Belleville P Popall M Applications of hybrid organic-inorganic nanocomposites Journal of Materials Chemistry 2005 15 3559 92

Cited by

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Related

Authors
Liu, D., Yang, F., Xiong, F., & Gu, N.
Affiliations
State Key Laboratory of Digital Medical Engineering (CN)
Corresponding author
  • Yang, Fang
  • Gu, Ning
ORCID
Venue
Theranostics
Publisher
Ivyspring International Publisher
Published
2016
Volume
6
Issue
9
Pages
1306-1323
ISSN
1838-7640 (ISSN-L)
DOI
10.7150/thno.14858
PMC
PMC4924501
OpenAlex
W2438292910
Cited by
1,066
References
176
Citations by year
2026: 80 · 2025: 125 · 2024: 136 · 2023: 108 · 2022: 128 · 2021: 125 · 2020: 128 · 2019: 100 · 2018: 83 · 2017: 47 · 2016: 6
FWCI
32.15
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Theranostics (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Keywords
smart drug delivery, targeted drug delivery, clinical translation, nanomedicine, polymeric nanoparticles, liposomes, metal oxide nanoparticles, exosomes, toxicity prediction, regulatory approval
MeSH terms
Theranostic Nanomedicine, Animals, Humans, Drug Delivery Systems, Nanoparticles, Drug Discovery, Molecular Targeted Therapy

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

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