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Review
. 2019 Jan 10;11(1):68.
doi: 10.3390/cancers11010068.

Targeted Delivery to Tumors: Multidirectional Strategies to Improve Treatment Efficiency

Olga M Kutova  1 , Evgenii L Guryev  2 , Evgeniya A Sokolova  3 , Razan Alzeibak  4 , Irina V Balalaeva  5   6
Affiliations
Review

Targeted Delivery to Tumors: Multidirectional Strategies to Improve Treatment Efficiency

Olga M Kutova et al. Cancers (Basel). .

Abstract

Malignant tumors are characterized by structural and molecular peculiarities providing a possibility to directionally deliver antitumor drugs with minimal impact on healthy tissues and reduced side effects. Newly formed blood vessels in malignant lesions exhibit chaotic growth, disordered structure, irregular shape and diameter, protrusions, and blind ends, resulting in immature vasculature; the newly formed lymphatic vessels also have aberrant structure. Structural features of the tumor vasculature determine relatively easy penetration of large molecules as well as nanometer-sized particles through a blood⁻tissue barrier and their accumulation in a tumor tissue. Also, malignant cells have altered molecular profile due to significant changes in tumor cell metabolism at every level from the genome to metabolome. Recently, the tumor interaction with cells of immune system becomes the focus of particular attention, that among others findings resulted in extensive study of cells with preferential tropism to tumor. In this review we summarize the information on the diversity of currently existing approaches to targeted drug delivery to tumor, including (i) passive targeting based on the specific features of tumor vasculature, (ii) active targeting which implies a specific binding of the antitumor agent with its molecular target, and (iii) cell-mediated tumor targeting.

Keywords: EPR-effect; active targeting; cancer treatment; cancer-specific molecular targets; cell-mediated targeting; passive targeting; targeted drug delivery.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Scheme illustrating the principle of passive drug delivery to the tumor. EPR effect: Permeability and Retention effect; UCNP: upconversion nanoparticles. The extravasation and penetration of nanoscale agents into the tumor is due to the disordered structure of the tumor vessels, their discontinuous endothelial lining and the disrupted integrity of the basement membrane. Irregular diameter and leakage of the walls of the newly formed lymphatic vessels impede the outflow of fluid and the removal of nano-sized agents from the tumor. Insets I and II indicate examples of passive drug delivery in vivo. I—Polymer particles based on water-soluble polymer brushes (polyimide-graft-polymethacrylic acid) are used to deliver photodynamic dye (tetra(4-fluorophenyl)tetracyano porphyrazine). The image was obtained by whole-body imaging 24 h after intravenous injection of a dye to BALB/c mouse with CT26 allograft (murine colorectal carcinoma) in the left thigh. The position of the tumor is indicated by an arrow. The fluorescence intensity of the dye is presented in the gradient red to yellow scale, where yellow corresponds to the maximum signal. II—Passive delivery of upconversion nanoparticles (UCNP) of composition, NaY:Yb:Tm:F4/NaYF4 covered with alternating copolymer of maleic anhydride and 1-octadecene (PMAO). Tumor and muscle tissue images were obtained ex vivo by confocal fluorescence microscopy 3 h after intravenous injection of UCNP-PMAO to a BALB/c mouse with SK-BR-3 xenograft (human breast adenocarcinoma). Purple signal corresponds to the UCNP photoluminescence. Scale bar 20 μm.
Figure 2
Figure 2
Scheme illustrating the principle of active drug delivery to the tumor. QD: quantum dots; scFv: single chain fragment variable. Active delivery implies covalent or non-covalent binding of the delivered agent to the moiety, which determines its selective interaction with specific molecules on the surface of target cells. This moiety can be attached directly to the delivered drug or to a nano-sized container loaded with a therapeutic drug. Insets I and II indicate examples of active drug delivery in vivo. I—Active delivery of NIR fluorescent quantum dots (QD) bound with anti-HER2 scFv (4D5scFv). Image of tumor tissue was obtained by confocal fluorescence microscopy 21 h after intravenous injection of QD-4D5scFv to BALB/c nude mice with SK-BR-3 xenograft (human breast adenocarcinoma). The red signal corresponds to QD photoluminescence. Scale bar 10 μm. II—Active delivery of upconversion nanoparticles (UCNP) of NaY:Yb:Tm:F4/NaYF4 composition bound with HER2-specific protein DARPin. The image was obtained by whole-body imaging 2 h after the intravenous (tail vein) injection of the nanocomplex BALB/c mouse with SK-BR-3 xenograft (human breast adenocarcinoma). The position of the tumor is indicated by an arrow. The red signal corresponds to the photoluminescence of the UCNP.
Figure 3
Figure 3
Scheme illustrating the principle of cell-mediated tumor targeting. Drug carriers may be tumor tropic cells: naive T-lymphocytes, primed T-lymphocytes, monocytes, neutrophilic granulocytes, macrophages, mesenchymal stem cells from bone marrow and umbilical cord blood, neural stem cells, and some other cell types. This approach involves the collection of autologous or donor material, loading/activation of the cells under ex vivo conditions, expansion to necessary quantities and introducing them back into the body. Cells can be successfully used to deliver low-molecular compounds, proteins, genetic material, nanoparticles and oncolytic viruses.
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