TAT peptide-based micelle system for potential active targeting of anti-cancer agents to acidic solid tumors

Abstract

A novel drug targeting system for acidic solid tumors has been developed based on ultra pH sensitive polymer and cell penetrating TAT. The delivery system consisted of two components: 1) A polymeric micelle that has a hydrophobic core made of Poly(L-lactic acid) (PLLA) and a hydrophilic shell consisting of Polyethylene Glycol (PEG) conjugated to TAT (TATmicelle), 2) An ultra pH sensitive diblock copolymer of poly(methacryloyl sulfadimethoxine) (PSD) and PEG (PSD-b-PEG). The anionic PSD is complexed with cationic TAT of the micelles to achieve the final carrier, which could systemically shield the micelles and expose them at slightly acidic tumor pH. TATmicelles had particle sizes between 20 to 45 nm and their critical micelle concentrations were 3.5 mg/L to 5.5 mg/ L. The TATmicelles, upon mixing with pH sensitive PSD-b-PEG, showed slight increase in particle size between pH 8.0 and 6.8 (60-90 nm), indicating complexation. As the pH was decreased (pH 6.6 to 6.0) two populations were observed, one that of normal TAT micelles (45 nm) and the other of aggregated hydrophobic PSD-b-PEG. Zeta potential measurements showed similar trend substantiating the shielding/deshielding process. Flowcytometry and confocal microscopy showed significantly higher uptake of TAT micelles at pH 6.6 compared to pH 7.4 indicating shielding at normal pH and deshielding at tumor pH. The flowcytometry indicated that the TAT not only translocates into the cells but is also seen on the surface of the nucleus. These results strongly indicate that the above drug loaded micelles would be able to target any hydrophobic drug near the nucleus.

Super pH-sensitive multifunctional polymeric micelle for tumor pHe specific TAT exposure and multidrug resistance

“…However, at pH 6.6 the PHSM pop-upTAT released 60 wt.% of the initial DOX amount and at pH 6.4 (e.g., endosomal pH) the PHSM pop-upTAT released approximately 78 wt.% of the initial DOX amount. These pHsensitive DOX release properties of PHSM pop-upTAT are due to the physical destabilization of the hydrophobic core (resulting from ionization of polyHis) as the pH decreases [20][21][22][23][24][25]. In addition, DOX release behaviors of the PHSM or PHSM TAT with pH were similar to that of the PHSM pop-upTAT (data not shown).…”

Cell-penetrating and cell-targeting peptides in drug delivery

“…In the peritumoral environment, pH can decrease to 6.8, inducing the neutralization of PSD charges, and full exposure of the CPP. The drug-loaded nanoparticle is internalized preferentially in the surrounding cells (from [94,95]). C) A CPP-procaspase fusion construct enters the cells.…”

“…More recently, ionic interactions between CPPs and their anionic counterparts have been exploited to temporally hide the cellular "sticky opportunism" of cationic CPPs during their transport towards the tumor site [94]. This delivery system consists of two components: a conventional hydrophobic core made of a polymer into which any chemotherapeutic molecule can be incorporated, and a peripheral hydrophilic layer composed of polyethylene glycol and the Tat peptide.…”

“…Such ionic interactions are expected to shield the cationic charges during delivery up to when the slightly acidic microenvironment of the tumor triggers the protonation of the anionic moiety. This induces the ionic dissociation and the subsequent exposure of the Tat peptide sequence, allowing the preferential internalization of the drugloaded polymer into the surrounding tumor cells [94] (Figure 1B). This strategy has been pursued using the very pH-sensitive sulfonamide (PSD) group [95].…”

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

“…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]. At normal blood pH, the poly(sulfonamide) is negatively charged and shields Tat peptide on micellar surface by electrostatic interactions.…”