“SMART” Drug Delivery Systems:  Double-Targeted pH-Responsive Pharmaceutical Nanocarriers

Abstract

In order to develop targeted pharmaceutical carriers additionally capable of responding certain local stimuli, such as decreased pH values in tumors or infarcts, targeted long-circulating PEGylated liposomes and PEG-phosphatidylethanolamine (PEG-PE)-based micelles have been prepared with several functions. First, they are capable of targeting a specific cell or organ by attaching the monoclonal antimyosin antibody 2G4 to their surface via pNP-PEG-PE moieties. Second, these liposomes and micelles were additionally modified with biotin or TAT peptide (TATp) moieties attached to the surface of the nanocarrier by using biotin-PE or TATp-PE or TATp-short PEG-PE derivatives. PEG-PE used for liposome surface modification or for micelle preparation was made degradable by inserting the pH-sensitive hydrazone bond between PEG and PE (PEG-Hz-PE). Under normal pH values, biotin and TATp functions on the surface of nanocarriers were "shielded" by long protecting PEG chains (pH-degradable PEG 2000 -PE or PEG 5000 -PE) or by even longer pNP-PEG-PE moieties used to attach antibodies to the nanocarrier (non-pH-degradable PEG 3400 -PE or PEG 5000 -PE). At pH 7.5-8.0, both liposomes and micelles demonstrated high specific binding with 2G4 antibody substrate, myosin, but very limited binding on an avidin column (biotin-containing nanocarriers) or internalization by NIH/3T3 or U-87 cells (TATp-containing nanocarriers). However, upon brief incubation (15-to-30 min) at lower pH values (pH 5.0-6.0) nanocarriers lost their protective PEG shell because of acidic hydrolysis of PEG-Hz-PE and acquired the ability to become strongly retained on avidin-column (biotin-containing nanocarriers) or effectively internalized by cells via TATp moieties (TATp-containing nanocarriers). We consider this result as the first step in the development of multifunctional stimuli-sensitive pharmaceutical nanocarriers.

Tumor pH-responsive flower-like micelles of poly(l-lactic acid)-b-poly(ethylene glycol)-b-poly(l-histidine)

“…More recently, pH-sensitive polymeric carriers have been used in targeted antitumor drug delivery [14][15][16][17][18][19][20][21][22][23][24][25], based on intrinsic differences between various solid tumors and the surrounding normal tissues in terms of their relative acidity [26]. The extracellular pH (pH e ) in most tumors is more acidic (pH 6.5-7.2) than in normal tissues [27][28][29].…”

“…Hydrazone and acetal bonds between the drug and the micelles can be cleaved by acidic pH [14][15][16], however these bonds are more labile at endo/lysosomal pH (pH 5.0-5.5) than at tumor pH e to accelerate drug release from the micelles [14][15][16]. On the other hand, smart micelles showing a pH-induced interior structural change [17][18] or physical destabilization [19][20][21][22][23][24][25] have recently been investigated and showed a high sensitivity to tumor pH e .…”

“…On the other hand, smart micelles showing a pH-induced interior structural change [17][18] or physical destabilization [19][20][21][22][23][24][25] have recently been investigated and showed a high sensitivity to tumor pH e . The physical change in the drugcarrier [17][18][19][20][21][22][23][24][25] seems more tunable to recognize small differences in pH like tumor pH e , compared to the systems that rely on chemical bonds [14][15][16]. Furthermore, translating the non-specific nature of cationic HIV Tat peptide to acidic solid tumor-specific by pH-dependent electrostatic shielding/deshielding with polymeric micelles is an attractive concept [31].…”

A review of mechanistic insight and application of pH-sensitive liposomes in drug delivery

“…Later on, it was found that altered pH in different locations such as tumor extracellular environments is advantageous in the design of pH-responsive liposomes for specific cancer cell targeting, enhanced cellular internalization and rapid intracellular drug release (Bertrand et al, 2010;Sawant et al, 2006). Figure 2 depicts the mechanism of drug delivery via pH-sensitive liposomes.…”

Classification of stimuli–responsive polymers as anticancer drug delivery systems

“…However, work is still needed on the sensitivity of these drug carriers to the applied stimuli. Some major drawbacks in the field may include the off-tumortargeting caused by non-specific stimuli such as overexpression of target enzymes in non-cancer cells (Spallarossa et al, 2006;Cheng et al, 2009) inaccurate utilization of stimuli such as uncontrolled depth of magnetic field and heating (Sawant et al, 2006;Zhu et al, 2009;Deng et al, 2011) and slow response to applied stimulus (Zhu et al, 2008;Wong et al, 2011).…”