Multifunctional and stimuli-sensitive pharmaceutical nanocarriers

Abstract

Currently used pharmaceutical nanocarriers, such as liposomes, micelles, and polymeric nanoparticles, demonstrate a broad variety of useful properties, such as longevity in the body; specific targeting to certain disease sites; enhanced intracellular penetration; contrast properties allowing for direct carrier visualization in vivo; stimuli-sensitivity, and others. Some of those pharmaceutical carriers have already made their way into clinic, while others are still under preclinical development. In certain cases, the pharmaceutical nanocarriers combine several of the listed properties. Long-circulating immunoliposomes capable of prolonged residence in the blood and specific target recognition represent one of the examples of this kind. The engineering of multifunctional pharmaceutical nanocarriers combining several useful properties in one particle can significantly enhance the efficacy of many therapeutic and diagnostic protocols. This paper considers the current status and possible future directions in the emerging area of multifunctional nanocarriers with primary attention on the combination of such properties as longevity, targetability, intracellular penetration, contrast loading, and stimuli-sensitivity.

Figure 1

The schematic structure of long-circulating targeted nanocarrier: 1 – nanocarrier; 2 – drug; 3 – sterically protecting polymer (usually, PEG) grafted on the surface of the nanocarrier; 4 – targeting ligand (antibody, folate, transferring) chemically coupled with distant tips of some of the protecting polymer grafted chains; 5 – specific receptor targeted with the attached ligand; 6 – cell membrane.

Figure 2

Schematic picture of different stimuli acting on the stimuli-sensitive nanocarrier and expected responses: 1 – nanocarrier; 2 – drug; 3 – protectine polymeric coating attached to the surface of the nanocarrier via pH-sensitive bonds could be detached and removed by the action of lowered pH in certain pathological areas (tumors) or inside cellular compartments (cytoplasm, endosome); 4 – temperature-sensitive coating or components of the carrier, which can be influenced by the heat (hyperthermia in certain pathological areas or the heat brought upon by an external source) to destabilize the carrier and allow for drug release; 5 – redox-sensitive coating or components of the carrier, which can be influenced by changing redox conditions (increased glutathione), for example by transforming –S-S-bonds into thiol groups, and allow for drug release; 6 – particles of magnetosensitive material (SPION), which can allow the whole nanocarrier to be transported to required site under the action of an external magnetic field.

Figure 3

Magneto-sensitive nanoparticles. PEG-PE micelles loaded with SPION concentrate in the vicinity of externally applied magnet.

Figure 4

A – Schematic structure of a double-targeted “smart” nanocarrier with temporarily “hidden” function, for example cell-penetrating peptide, and “shielding” polymeric coat (with or without targeting antibody attached to it) providing longevity in the blood and specific target (tumor) accumulation and preventing the hidden function from the premature interaction with target cells. Polymeric chains are attached to the carrier surface via low pH-degradable bonds. After the accumulation in the tumor due to PEG (longevity) and/or antibody (specific targeting), pH-dependent de-shielding of the temporarily hidden cell-penetrating function allow for carrier penetration inside tumor cells. B – Interaction of “smart” TAT peptide-modified liposomes. Rhodamin-labeled TAT-liposomes are effectively taken by cells. The attachment of PEG-chains to the liposome surface (18% mol) sterically shields TAT finction and TAT-mediated liposome uptake is almost completely blocked. If, however, PEG is attached to the liposome surface via pH-sensitive bonds, its brief incubation at the lowered pH results in the elimination of PEG chains from the liposome surface, de-blocking TAT function and good TAT-mediated uptake of the liposomes by cells. Modified from [234-236].

Figure 5

Combination of the longevity, targetability, and contrast function. Radiolabeled (¹¹¹In) long-circulating (PEG) liposomes (LCL) modified with a tumor-targeted ligand (cancer-specific monoclonal antibody 2C5) demonstrate an enhanced tumor accumulation – A. This can be used for the fast and specific tumor visualization by gamma-scintigraphy (mice) – B. Modified from [264].