Antitumor Drug Delivery Modulated by A Polymeric Micelle with an Upper Critical Solution Temperature

Abstract

Thermally sensitive polymeric nanocarriers were developed to optimize the release profile of encapsulated compounds to improve treatment efficiency. However, when referring to thermally sensitive polymeric nanocarriers, this usually means systems fabricated from lower critical solution temperature (LCST) polymers, which have been intensively studied. To extend the field of thermally sensitive polymeric nanocarriers, we for the first time fabricated a polymeric drug delivery system having an upper critical solution temperature (UCST) of 43 °C based on an amphiphilic polymer poly(AAm-co-AN)-g-PEG. The resulting polymeric micelles could effectively encapsulate doxorubicin and exhibited thermally sensitive drug release both in vitro and in vivo. A drastically improved anticancer efficiency (IC50 decreased from 4.6 to 1.6 μg mL(-1), tumor inhibition rate increased from 55.6% to 92.8%) was observed. These results suggest that UCST-based drug delivery can be an alternative to thermally sensitive LCST-based drug delivery systems for an enhanced antitumor efficiency.

Understanding the UCST-type transition of P(AAm-co-AN) in H2O and D2O: dramatic effects of solvent isotopes

“…Due to the strong sensitivity of phase transition behavior to electrolytes (ions) of charged polymers, uncharged UCST-type polymers relying on hydrogen bonding, whose thermosensitivity is relativity stable, present more promising candidates for biomedical applications. 19,20 However, to the best of our knowledge, comprehensive investigations of the UCST-type transition behavior of P(AAm-co-AN) in water at the molecular level are still lacking. 15,16 Since then, it has aroused increasing interest in both fundamental and applied arena.…”

A Synthetic, Transiently Thermoresponsive Homopolymer with UCST Behaviour within a Physiologically Relevant Window

“…[16] Similar to their LCST counterparts,p olymers that exhibit UCST behaviour in af ully aqueous environmentthat is,w ithout the requirement of co-solvents-and exhibit ag lobule-to-coil transformation close to the physiological temperature of 37 8 8Cc ould be attractive for biomedical applications,but are much less reported. [17] Generally,UCST polymers exhibit thermoresponsiveness on the basis of cohesive enthalpic interactions between polymer chains, such as hydrogen bonds and electrostatic interactions. [18][19][20] Thel atter are commonly based on polybetaines or zwitterionic polymers,w hich lose their UCST behaviour in physiological media owing to screening of the electrostatic charges.T herefore,m ost UCST polymers operating within ap hysiologically relevant context are based on hydrogen bond formation between amide-or urea-based repeating units in the polymer backbone.…”

K+‐Responsive Block Copolymer Micelles for Targeted Intracellular Drug Delivery

“…The fluorescence of Nile red encapsulated into the micelles cannot be detected under fluorescence microscope. Only when being released from the micelles and interacts with the cytosol lipid, the fluorescence of Nile red can be detected . As presented in Figure 11 , in fluorescence images of both HSC‐T6 and HepG2 cells incubated with Nile red‐loaded PENB‐15% micelles for the same period of time, the red fluorescence from Nile red is obviously distributed around the blue nucleus of cells.…”

“…According to the variety of stimuli, the stimuli‐responsive micelles can be classified into exogenous and endogenous types . The exogenous‐type micelles could release the drugs in response to environment stimuli in vitro such as temperature, magnetic field, ultrasound, and light . However, these stimuli usually act on the entire lesion tissues and the drug release often occurs both inside and outside of cells, thus resulting in inaccurate drug release and low bioavailability of drugs.…”