Temperature-Responsive Smart Nanocarriers for Delivery Of Therapeutic Agents: Applications and Recent Advances

Abstract

Smart drug delivery systems (DDSs) have attracted the attention of many scientists, as carriers that can be stimulated by changes in environmental parameters such as temperature, pH, light, electromagnetic fields, mechanical forces, etc. These smart nanocarriers can release their cargo on demand when their target is reached and the stimulus is applied. Using the techniques of nanotechnology, these nanocarriers can be tailored to be target-specific, and exhibit delayed or controlled release of drugs. Temperature-responsive nanocarriers are one of most important groups of smart nanoparticles (NPs) that have been investigated during the past decades. Temperature can either act as an external stimulus when heat is applied from the outside, or can be internal when pathological lesions have a naturally elevated termperature. A low critical solution temperature (LCST) is a special feature of some polymeric materials, and most of the temperature-responsive nanocarriers have been designed based on this feature. In this review, we attempt to summarize recent efforts to prepare innovative temperature-responsive nanocarriers and discuss their novel applications.

Keywords: LCST/UCST behavior; anticancer delivery; characterization; dual/multi responsive; gene delivery; smart drug delivery systems; synthesis; temperature-responsive nanocarriers.

Figure 1

Shrinkage of a loaded hydrogel and release of drug during LCST behavior. Reprinted with permission from ref . Copyright 2015 Royal Society of Chemistry (RSC).

Figure 2

Diffusion paths of water molecules in PNIPAAm-g-PEO.

Figure 3

Phase transition behavior of amino-terminated PNIPAAm (PNIPAAm-NH2) (2 wt %) and CMC-g-PNIPAAm (2 wt %) in PBS: (a) heating cycle from 25 to 35 °C and (b) cooling cycle from 35 to 25 °C. Reprinted with permission from ref . Copyright 2011 Elsevier.

Figure 4

Schematic representation of hydrogels loaded with alginate microspheres.

Figure 5

Schematic of drug release from a temperature responsive core–shell nanocarrier: (a) below LCST temperature, (b) above LCST temperature.

Figure 6

Photoemulsion polymerization of PS-NIPA core–shell particles. Reprinted with permission from ref . Copyright 2006 John Wiley & Sons.

Figure 7

Schematic of synthesis of CS-g-PSBMA. Reprinted with permission from ref . Copyright 2015 Royal Society of Chemistry (RSC).

Figure 8

On–off valve mechanism represented by PC-g-P(NIPAAm-co-AAc) grafted onto microporous composite films. Reprinted with permission from ref . Copyright 2012 Springer.

Figure 9

Micelle formation occurs if the concentration of polymer is greater than CMC. Above the LCST, the thermosensitive block shrinks, inducing the release of incorporated agents. The nanocarrier can target tumor cells overexpressing FR, and rapidly intracellular drug release will be triggered by heating (40 °C) upon LCST on the tumor tissue. Reprinted with permission from ref . Copyright 2014 American Chemical Society.

Figure 10

Stages of gene transfection by cationic thermoresponsive polymers.

Figure 11

(a) Schematic representing the self-assembly of PHis-PLGA-PEG-PLGA-Phis copolymer micellar nanocarrier and its dual responsiveness regarding temperature and pH stimulus, (b, c) in vitro DOX release from the nanocarrier in different pH amounts and temperatures. Reprinted with permission from ref . Copyright 2014 Elsevier.

Figure 12

In situ fabrication of core cross-linked (CCL) drug-loaded micelles. Reprinted with permission from ref . Copyright 2014 Elsevier.

Figure 13

Schematic of (a) NIR triggered drug release of encapsulated DOX and ICG from polymeric nanogels via photoinduced thermoresponsive relaxation of β-CD and AD-based host–guest interactions. Reprinted with permission from ref . Copyright 2015 Royal Society of Chemistry (RSC). (b) NIR-triggered thermoresponsive drug release from Cu_1.75S@p(NIPAM-MAA) NPs. Reprinted with permission from ref . Copyright 2015 Springer.