Analysis on the current status of targeted drug delivery to tumors

Abstract

Targeted drug delivery to tumor sites is one of the ultimate goals in drug delivery. Recent progress in nanoparticle engineering has certainly improved drug targeting, but the results are not as good as expected. This is largely due to the fact that nanoparticles, regardless of how advanced they are, find the target as a result of blood circulation, like the conventional drug delivery systems do. Currently, the nanoparticle-based drug delivery to the target tumor tissues is based on wrong assumptions that most of the nanoparticles, either PEGylated or not, reach the target by the enhanced permeation and retention (EPR) effect. Studies have shown that so-called targeting moieties, i.e., antibodies or ligands, on the nanoparticle surface do not really improve delivery to target tumors. Targeted drug delivery to tumor sites is associated with highly complex biological, mechanical, chemical and transport phenomena, of which characteristics vary spatiotemporally. Yet, most of the efforts have been focused on design and surface manipulation of the drug carrying nanoparticles with relatively little attention to other aspects. This article examines the current misunderstandings and the main difficulties in targeted drug delivery.

Fig. 1

Delivery of intravenously (iv) administered nanoparticles to the target tumor. (A)The majority of the administered nanoparticles end up in the non-target organs and only a small fraction reaches the target tumor. (B) The nanoparticles circulate in blood to reach target tumors by extravasation. The drug leaks out of the nanoparticles during circulation, and the majority of the nanoparticles end up in non-target organs. The nanoparticles reaching the target tumor face a tumor microenvironment different from that of normal tissues.

Fig. 2

Tumor pharmacokinetics of anti-HER2 immunoliposomes (Anti-HERs ILs) versus control PEGylated liposomes (Ls) in s.c. BT-474 breast cancer xenografts in nude mice. (Inset) uptake of anti-HER2 immunoliposomes (cross-hatched column on the right) versus control liposomes (empty column on the left) in HER2-overexpressing breast cancer cells (SK-Br-3) in vitro (redrawn from reference [8]).

Fig. 3

Blood kinetics of ¹¹¹In labeled temperature-sensitive liposomes containing doxorubicin. The percentage of the injected dose (%ID) is plotted per gram blood (left axis) and for the total blood (right axis) (redrawn from reference [29]).

Fig. 4

Penetration of anticancer drugs as a function of time through multicellular layers derived from human colon carcinoma cell lines. The penetration of doxorubicin (A), 5-FU (B), methotrexate (C), and paclitaxel (D) through highly packed (Ea, ●) and loosely packed (Ra, ○) sublines (redrawn from reference [5]).

Fig. 5

Interstitial fluid pressure (IFP) and velocity distribution of a tumor grown in subcutaneous tissue. The center and the boundary of the tumor are indicated by r/R=0, and r/R=1, respectively. IFP () stays at elevated level at the interior of the tumor and sharply decreases at the periphery. Due to this pressure gradient, radially outward interstitial fluid motion is induced at approximately 0.02 µm/s (). This outward convection in conjunction with less extravasation due to elevated IFP is believed to lead insufficient delivery of therapeutic agents (redrawn from reference [38]).