Development of next-generation macromolecular drugs based on the EPR effect: challenges and pitfalls

Nakamura, Hideaki; Fang, Jun; Maeda, Hiroshi

doi:10.1517/17425247.2014.955011

Cited by 211 publications

(162 citation statements)

References 64 publications

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“…The passive targeting of nanomaterials was the principal advantage in earlier studies. On the one hand, drug solubility and stability can be improved and the circulation time can be prolonged by conjugation with nanovectors, which can also induce the selective transport of drugs to tumor sites based on the enhanced permeability and retention effect [17,18]. Numerous inorganic [19,20] and organic nanocarriers [21,22] have been developed for drug delivery, but their potential hazards to human health and the environment have greatly limited their widespread clinical application [23,24].…”

Section: Discussionmentioning

confidence: 99%

Overcoming Drug Resistance in Colon Cancer by Aptamer-Mediated Targeted Co-Delivery of Drug and siRNA Using Grapefruit-Derived Nanovectors

Yan

Tao

Jiang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Multidrug resistance (MDR) is the most common cause of chemotherapy failure. Upregulation of P-glycoprotein (P-gp) is one of the main mechanisms underlying MDR. Methods: In this study, we developed a targeted drug and small interfering (si)RNA co-delivery system based on specific aptamer-conjugated grapefruit-derived nanovectors (GNVs) that we tested in MDR LoVo colon cancer cells. The internalization of nanovectors in cancer cells was tested by fluorescence microscopy and flow cytometry. The anti-cancer activity in vitro was determined by colony formation and cell apoptosis assays. The biodistribution of nanovectors was analyzed by live imaging and the anti-cancer activity in vivo was observed. Results: GNVs loaded with aptamer increased doxorubicin (Dox) accumulation in MDR LoVo cells, an effect that was abolished by pretreatment with DNase. The LA1 aptamer effectively promoted nanovector internalization into cells at 4°C and increased the targeted delivery of Dox to tumors. Constructs harboring Dox, LA1, and P-gp siRNA more effectively inhibited proliferation and enhanced apoptosis in cultured MDR LoVo cells while exhibiting more potent anti-tumor activity in vivo than free Dox or GNVs loaded with Dox alone or in conjunction with LA1, an effect that was associated with downregulation of P-gp expression. Conclusion: This GNV-based system may be an effective strategy for overcoming MDR in clinical settings.

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Section: Discussionmentioning

confidence: 99%

Overcoming Drug Resistance in Colon Cancer by Aptamer-Mediated Targeted Co-Delivery of Drug and siRNA Using Grapefruit-Derived Nanovectors

Yan

Tao

Jiang

et al. 2018

Cell Physiol Biochem

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“…Due to exceptional physical, chemical, and optical characteristics, nanoparticles are ideal candidates for early cancer diagnostics and great benefits are anticipated for cancer therapy. Although it is claimed that nanoparticles should accumulate specifically inside the tumor due to the enhanced permeability and retention effect, 47 passive accumulation lacks specificity to tumors. 48 As a result, functionalization of nanoparticles using various targeting molecules -ligands, peptides, antibodies, and so on -became a natural choice.…”

Section: Discussionmentioning

confidence: 99%

Skin-derived mesenchymal stem cells as quantum dot vehicles to tumors

Dapkutė¹,

Steponkienė²,

Bulotienė³

et al. 2017

IJN

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Purpose Cell-mediated delivery of nanoparticles is emerging as a new method of cancer diagnostics and treatment. Due to their inherent regenerative properties, adult mesenchymal stem cells (MSCs) are naturally attracted to wounds and sites of inflammation, as well as tumors. Such characteristics enable MSCs to be used in cellular hitchhiking of nanoparticles. In this study, MSCs extracted from the skin connective tissue were investigated as transporters of semiconductor nanocrystals quantum dots (QDs). Materials and methods Cytotoxicity of carboxylated CdSe/ZnS QDs was assessed by lactate dehydrogenase cell viability assay. Quantitative uptake of QDs was determined by flow cytometry; their intracellular localization was evaluated by confocal microscopy. In vitro tumor-tropic migration of skin-derived MSCs was verified by Transwell migration assay. For in vivo migration studies of QD-loaded MSCs, human breast tumor-bearing immunodeficient mice were used. Results QDs were found to be nontoxic to MSCs in concentrations no more than 16 nM. The uptake studies showed a rapid QD endocytosis followed by saturating effects after 6 h of incubation and intracellular localization in the perinuclear region. In vitro migration of MSCs toward MDA-MB-231 breast cancer cells and their conditioned medium was up to nine times greater than the migration toward noncancerous breast epithelial cells MCF-10A. In vivo, systemically administered QD-labeled MSCs were mainly located in the tumor and metastatic tissues, evading most healthy organs with the exception being blood clearance organs (spleen, kidneys, liver). Conclusion Skin-derived MSCs demonstrate applicability in cell-mediated delivery of nanoparticles. The findings presented in this study promise further development of a cell therapy and nanotechnology-based tool for early cancer diagnostics and therapy.

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“…The EPR effect is a well-known phenomenon that describes the accumulation of nanoscale drug formulations at sites of inflammation and solid tumors due to the leaky tumor vasculature and suppressed lymphatic system (Maeda, 2012). Such leaky vessels are not typically found in normal healthy tissues, thereby allowing for a more targeted drug delivery (Nakamura et al, 2015). Heterogeneity of solid tumors among patients and interpatient variability of nanoparticle PK create additional challenges in predicting the safety and efficacy of a nanomedicine formulation (Zamboni et al, 2009;Sidone et al, 2007;Caron et al, 2011;Prabhakar et al, 2013).…”

Section: Nanoparticle Pkmentioning

confidence: 99%

When Is It Important to Measure Unbound Drug in Evaluating Nanomedicine Pharmacokinetics?

2016

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Nanoformulations have become important tools for modifying drug disposition, be it from the perspective of enabling prolonged drug release, protecting the drug molecule from metabolism, or achieving targeted delivery. When examining the in vivo pharmacokinetic properties of these formulations, most investigations either focus on systemic concentrations of total (encapsulated plus unencapsulated) drug, or concentrations of encapsulated and unencapsulated drug. However, it is rare to find studies that differentiate between protein-bound and unbound (free) forms of the unencapsulated drug. In light of the unique attributes of these formulations, we cannot simply assume it appropriate to rely upon the protein-binding properties of the traditionally formulated or legacy drug when trying to define the pharmacokinetic or pharmacokinetic/pharmacodynamic characteristics of these nanoformulations. Therefore, this commentary explores reasons why it is important to consider not only unencapsulated drug, but also the portion of unencapsulated drug that is not bound to plasma proteins. Specifically, we highlight those situations when it may be necessary to include measurement of unencapsulated, unbound drug concentrations as part of the nanoformulation pharmacokinetic evaluation.

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Development of next-generation macromolecular drugs based on the EPR effect: challenges and pitfalls

Abstract: Tumor selective delivery of antitumor drugs based on the EPR effect can be accomplished and augmented by modulating the tumor environment. This methodology is favorable not only for tumor therapy but also for tumor imaging.

Cited by 211 publications

References 64 publications

Overcoming Drug Resistance in Colon Cancer by Aptamer-Mediated Targeted Co-Delivery of Drug and siRNA Using Grapefruit-Derived Nanovectors

Overcoming Drug Resistance in Colon Cancer by Aptamer-Mediated Targeted Co-Delivery of Drug and siRNA Using Grapefruit-Derived Nanovectors

Skin-derived mesenchymal stem cells as quantum dot vehicles to tumors

When Is It Important to Measure Unbound Drug in Evaluating Nanomedicine Pharmacokinetics?

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