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Current Approaches for Improving Intratumoral Accumulation and Distribution of Nanomedicines.

Durymanov MO, Rosenkranz AA, Sobolev AS - Theranostics (2015)

Bottom Line: The ability of nanoparticles and macromolecules to passively accumulate in solid tumors and enhance therapeutic effects in comparison with conventional anticancer agents has resulted in the development of various multifunctional nanomedicines including liposomes, polymeric micelles, and magnetic nanoparticles.These "smart" systems have enabled highly effective delivery of drugs, genes, shRNA, radioisotopes, and other therapeutic molecules.However, the resulting therapeutically relevant local concentrations of anticancer agents are often insufficient to cause tumor regression and complete elimination.

View Article: PubMed Central - PubMed

Affiliation: 1. Department of Molecular Genetics of Intracellular Transport, Institute of Gene Biology, Russian Academy of Sciences, 34/5, Vavilov St., 199334, Moscow, Russia.

ABSTRACT
The ability of nanoparticles and macromolecules to passively accumulate in solid tumors and enhance therapeutic effects in comparison with conventional anticancer agents has resulted in the development of various multifunctional nanomedicines including liposomes, polymeric micelles, and magnetic nanoparticles. Further modifications of these nanoparticles have improved their characteristics in terms of tumor selectivity, circulation time in blood, enhanced uptake by cancer cells, and sensitivity to tumor microenvironment. These "smart" systems have enabled highly effective delivery of drugs, genes, shRNA, radioisotopes, and other therapeutic molecules. However, the resulting therapeutically relevant local concentrations of anticancer agents are often insufficient to cause tumor regression and complete elimination. Poor perfusion of inner regions of solid tumors as well as vascular barrier, high interstitial fluid pressure, and dense intercellular matrix are the main intratumoral barriers that impair drug delivery and impede uniform distribution of nanomedicines throughout a tumor. Here we review existing methods and approaches for improving tumoral uptake and distribution of nano-scaled therapeutic particles and macromolecules (i.e. nanomedicines). Briefly, these strategies include tuning physicochemical characteristics of nanomedicines, modulating physiological state of tumors with physical impacts or physiologically active agents, and active delivery of nanomedicines using cellular hitchhiking.

No MeSH data available.


Related in: MedlinePlus

Influence of nanomedicine functionalization with target moieties on tumor accumulation. Targeted nanomedicines extravasate into tumor interstitium and bind/internalize into cancer cells (green) due to antigen-antibody/ligand-receptor interactions. Untargeted nanomedicines can bind and internalize into cancer (green) and non-cancer (yellow and blue) cells due to unspecific surface adsorption; endotheliocytes are shown in red. However, a significant part can be washed out from the extravascular compartment back to the blood circulation, resulting in lower tumor accumulation.
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Figure 1: Influence of nanomedicine functionalization with target moieties on tumor accumulation. Targeted nanomedicines extravasate into tumor interstitium and bind/internalize into cancer cells (green) due to antigen-antibody/ligand-receptor interactions. Untargeted nanomedicines can bind and internalize into cancer (green) and non-cancer (yellow and blue) cells due to unspecific surface adsorption; endotheliocytes are shown in red. However, a significant part can be washed out from the extravascular compartment back to the blood circulation, resulting in lower tumor accumulation.

Mentions: For targeted delivery of nanomedicines to cancer cells, molecular recognition processes, like ligand-receptor interactions, can be exploited. Usually, this approach aims for i) strong binding of nanotherapeutics to target cells and prolonged retention in tumor site, or ii) receptor-mediated internalization into cancer cells that is necessary for therapeutic nanovehicles containing nucleic acids (plasmid DNA, shRNA, mRNA) and locally acting molecules like Auger electron emitters or photosensitizers. In any event, modification of nanoparticles with a ligand often leads to their enhanced accumulation in tumor as compared with untargeted counterparts 42, 68-70. However, this approach does not always augment nanomedicine deposition in tumors, which has been shown for targeted gold nanoparticles 71, liposomes 72,73, polymeric gene delivery vehicles (polyplexes) 10, and polymeric micelles 42 in comparison with their untargeted analogs. Most likely, discrepancies in the data can be explained by the fact that total accumulation is the integral characteristic of nanoparticle delivery. It is clear that the process of nanomedicine transport subdivides into some steps including vascular transport, extravasation, and interstitial transport. Detailed analysis of nanoparticle microdistribution revealed that the major part of “in tumor accumulated” nanoparticles reside on the vessel wall surface or in close proximity to the blood vessels 10, 40-42, 47, 48, which does not exclude their washout back to the blood circulation (Fig. 1). This means that strong binding with cancer cells is one of the main causes of superior tumor accumulation rate of targeted nanomedicines (Fig. 1). It should be noted that targeting mainly prevents the washout of the smaller nanoparticles from the extravascular compartment 42, 73, especially in slow flow tumor regions 73. Therefore, high expression of target receptors in tumor and highly effective nanoparticle targeting are crucial conditions for prolonged retention of targeted nanomedicines in a tumor. The influence of expression level of target EGF receptors (EGFR) was evaluated in two breast murine tumor models with high (106 EGFR per cell) and low (104 EGFR per cell) level of EGFR expression. As a result, the greater accumulation of EGF-modified polymeric micelles compared with unmodified ones was observed only in the case of an EGFR-overexpressing model 42, 74. The importance of the degree of nanoparticle targeting has been demonstrated for magnetic nanoparticles with spherical and elongated shape. Unlike spherical, worm-like shape provides a more effective scaffold to generate multivalent interactions of ligand moieties and receptors, resulting in enhancement of targeted efficiency and decrease in washout from a tumor 75. Thus, low expression of target receptors and/or insufficient targeting of nanomedicines will lead to the same tumor deposition of targeted and untargeted nanoparticles. Even so, the benefit of ligand targeting can be illustrated by our own investigations of gene delivery into Cloudman S91 melanoma tumors (4,500 melanocortin receptors per cell) using polyplex nanoparticles. We found no differences in tumor accumulation and microdistribution of targeted polyplexes containing melanocortin receptor-1-specific peptide and untargeted ones. However, targeted polyplexes cause superior transfection in tumor 10, because the faster cellular uptake for polyplexes, provided by inclusion of a ligand into the polymeric part, is preferred for successful gene transfer 76, 77. A similar effect has been demonstrated in case of 100-nm siRNA nanoparticles 78. There is also a noteworthy fact that ligand targeting of PEGylated gene delivery vehicles makes it possible to overcome the above-mentioned “PEG-dilemma” by an increase in receptor-mediated internalization resulting in more effective gene therapy.


Current Approaches for Improving Intratumoral Accumulation and Distribution of Nanomedicines.

Durymanov MO, Rosenkranz AA, Sobolev AS - Theranostics (2015)

Influence of nanomedicine functionalization with target moieties on tumor accumulation. Targeted nanomedicines extravasate into tumor interstitium and bind/internalize into cancer cells (green) due to antigen-antibody/ligand-receptor interactions. Untargeted nanomedicines can bind and internalize into cancer (green) and non-cancer (yellow and blue) cells due to unspecific surface adsorption; endotheliocytes are shown in red. However, a significant part can be washed out from the extravascular compartment back to the blood circulation, resulting in lower tumor accumulation.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4493538&req=5

Figure 1: Influence of nanomedicine functionalization with target moieties on tumor accumulation. Targeted nanomedicines extravasate into tumor interstitium and bind/internalize into cancer cells (green) due to antigen-antibody/ligand-receptor interactions. Untargeted nanomedicines can bind and internalize into cancer (green) and non-cancer (yellow and blue) cells due to unspecific surface adsorption; endotheliocytes are shown in red. However, a significant part can be washed out from the extravascular compartment back to the blood circulation, resulting in lower tumor accumulation.
Mentions: For targeted delivery of nanomedicines to cancer cells, molecular recognition processes, like ligand-receptor interactions, can be exploited. Usually, this approach aims for i) strong binding of nanotherapeutics to target cells and prolonged retention in tumor site, or ii) receptor-mediated internalization into cancer cells that is necessary for therapeutic nanovehicles containing nucleic acids (plasmid DNA, shRNA, mRNA) and locally acting molecules like Auger electron emitters or photosensitizers. In any event, modification of nanoparticles with a ligand often leads to their enhanced accumulation in tumor as compared with untargeted counterparts 42, 68-70. However, this approach does not always augment nanomedicine deposition in tumors, which has been shown for targeted gold nanoparticles 71, liposomes 72,73, polymeric gene delivery vehicles (polyplexes) 10, and polymeric micelles 42 in comparison with their untargeted analogs. Most likely, discrepancies in the data can be explained by the fact that total accumulation is the integral characteristic of nanoparticle delivery. It is clear that the process of nanomedicine transport subdivides into some steps including vascular transport, extravasation, and interstitial transport. Detailed analysis of nanoparticle microdistribution revealed that the major part of “in tumor accumulated” nanoparticles reside on the vessel wall surface or in close proximity to the blood vessels 10, 40-42, 47, 48, which does not exclude their washout back to the blood circulation (Fig. 1). This means that strong binding with cancer cells is one of the main causes of superior tumor accumulation rate of targeted nanomedicines (Fig. 1). It should be noted that targeting mainly prevents the washout of the smaller nanoparticles from the extravascular compartment 42, 73, especially in slow flow tumor regions 73. Therefore, high expression of target receptors in tumor and highly effective nanoparticle targeting are crucial conditions for prolonged retention of targeted nanomedicines in a tumor. The influence of expression level of target EGF receptors (EGFR) was evaluated in two breast murine tumor models with high (106 EGFR per cell) and low (104 EGFR per cell) level of EGFR expression. As a result, the greater accumulation of EGF-modified polymeric micelles compared with unmodified ones was observed only in the case of an EGFR-overexpressing model 42, 74. The importance of the degree of nanoparticle targeting has been demonstrated for magnetic nanoparticles with spherical and elongated shape. Unlike spherical, worm-like shape provides a more effective scaffold to generate multivalent interactions of ligand moieties and receptors, resulting in enhancement of targeted efficiency and decrease in washout from a tumor 75. Thus, low expression of target receptors and/or insufficient targeting of nanomedicines will lead to the same tumor deposition of targeted and untargeted nanoparticles. Even so, the benefit of ligand targeting can be illustrated by our own investigations of gene delivery into Cloudman S91 melanoma tumors (4,500 melanocortin receptors per cell) using polyplex nanoparticles. We found no differences in tumor accumulation and microdistribution of targeted polyplexes containing melanocortin receptor-1-specific peptide and untargeted ones. However, targeted polyplexes cause superior transfection in tumor 10, because the faster cellular uptake for polyplexes, provided by inclusion of a ligand into the polymeric part, is preferred for successful gene transfer 76, 77. A similar effect has been demonstrated in case of 100-nm siRNA nanoparticles 78. There is also a noteworthy fact that ligand targeting of PEGylated gene delivery vehicles makes it possible to overcome the above-mentioned “PEG-dilemma” by an increase in receptor-mediated internalization resulting in more effective gene therapy.

Bottom Line: The ability of nanoparticles and macromolecules to passively accumulate in solid tumors and enhance therapeutic effects in comparison with conventional anticancer agents has resulted in the development of various multifunctional nanomedicines including liposomes, polymeric micelles, and magnetic nanoparticles.These "smart" systems have enabled highly effective delivery of drugs, genes, shRNA, radioisotopes, and other therapeutic molecules.However, the resulting therapeutically relevant local concentrations of anticancer agents are often insufficient to cause tumor regression and complete elimination.

View Article: PubMed Central - PubMed

Affiliation: 1. Department of Molecular Genetics of Intracellular Transport, Institute of Gene Biology, Russian Academy of Sciences, 34/5, Vavilov St., 199334, Moscow, Russia.

ABSTRACT
The ability of nanoparticles and macromolecules to passively accumulate in solid tumors and enhance therapeutic effects in comparison with conventional anticancer agents has resulted in the development of various multifunctional nanomedicines including liposomes, polymeric micelles, and magnetic nanoparticles. Further modifications of these nanoparticles have improved their characteristics in terms of tumor selectivity, circulation time in blood, enhanced uptake by cancer cells, and sensitivity to tumor microenvironment. These "smart" systems have enabled highly effective delivery of drugs, genes, shRNA, radioisotopes, and other therapeutic molecules. However, the resulting therapeutically relevant local concentrations of anticancer agents are often insufficient to cause tumor regression and complete elimination. Poor perfusion of inner regions of solid tumors as well as vascular barrier, high interstitial fluid pressure, and dense intercellular matrix are the main intratumoral barriers that impair drug delivery and impede uniform distribution of nanomedicines throughout a tumor. Here we review existing methods and approaches for improving tumoral uptake and distribution of nano-scaled therapeutic particles and macromolecules (i.e. nanomedicines). Briefly, these strategies include tuning physicochemical characteristics of nanomedicines, modulating physiological state of tumors with physical impacts or physiologically active agents, and active delivery of nanomedicines using cellular hitchhiking.

No MeSH data available.


Related in: MedlinePlus