A thermally targeted elastin-like polypeptide-doxorubicin conjugate overcomes drug resistance

Abstract

The ability of cancer cells to become simultaneously resistant to different drugs, a trait known as multidrug resistance, remains a major obstacle for successful anticancer therapy. One major mechanism of resistance involves cellular drug efflux by expression of P-glycoprotein (P-gp), a membrane transporter with a wide variety of substrates. Anthracyclines are especially prone to induction of resistance by the P-gp mechanism. P-gp mediated resistance is often confronted by use of P-gp inhibitors, synthesis of novel analogs, or conjugating drugs to macromolecular carriers in order to circumvent the efflux mechanism. In this report, the effect of free and Elastin-like polypeptide (ELP) bound doxorubicin (Dox) on the viability of sensitive (MES-SA and MCF-7) and multidrug resistant (MES-SA/Dx5 and NCI/ADR-RES) human carcinoma cells was studied in vitro. The resistant MES-SA/Dx5 cells demonstrated about 70 times higher resistance to free Dox than the sensitive MES-SA cells, and the NCI/ADR-RES cells were about 30 fold more resistant than the MCF-7 cells. However, the ELP-bound Dox was equally cytotoxic in both sensitive and resistant cell lines. The ELP-bound Dox was shown to accumulate in MES-SA/Dx5 cells, as opposed to free Dox, which was rapidly pumped out by the P-gp transporter. Since ELP is a thermally responsive carrier, the effect of hyperthermia on the cytotoxicity of the ELP-Dox conjugate was investigated. Both cytotoxicity and apoptosis were enhanced by hyperthermia in the Dox resistant cells. The results suggest that ELP-Dox conjugates may provide a means to thermally target solid tumors and to overcome drug resistance in cancer cells.

A thermally responsive biopolymer conjugated to an acid-sensitive derivative of paclitaxel stabilizes microtubules, arrests cell cycle, and induces apoptosis

“…In contrast, although SynB1-ELP1-Ptx inhibits MCF-7 survival with a relatively higher EC 50 of 822.7 nM, it inhibits MCF TAX survival with an EC 50 that is only 14-fold higher (11.6 μM) ( Table 2). SynB1-ELP1-Ptx at least partially seems to overcome drug resistance perhaps due to the circumvention of the P-gp pump [29].…”

Renal Therapeutic Angiogenesis Using a Bioengineered Polymer-Stabilized Vascular Endothelial Growth Factor Construct

“…This facilitates their modification for fusion with peptides and protein-based therapeutics prolonging their t 1/2 and tissue residence time, protecting them from proteolysis, and providing an excellent opportunity for developing tailored treatments. [8][9][10][11] ELPs naturally accumulate at high levels in kidney and liver tissues. We have recently generated and characterized in vitro an ELP fusion with human VEGF.…”

Nanotechnological Approaches to Therapeutic Delivery Using Elastin-Like Recombinamers

“…32 In another experiment, doxorubicin was conjugated via cysteine residues and intracellular cleavage of the drug was achieved by either an acid-labile hydrazine bond 33 or an enzymatic reaction. 34 In this case, a Tat domain, a cationic cell-penetrating peptide (CPP) derived from the trans-activating protein found in HIV-1, was fused to the ELR to enhance cellular uptake, along with the GFLG tetrapeptide linker to act as a substrate for lysosomal cathepsin proteases, thus allowing the release of the drug after endocytosis. The cytotoxicity of this "smart" system was tested in vitro, and the results showed that ELR-Dox was cytotoxic towards both non-and Dox-resistant carcinoma cell lines, being able to bypass the P-glycoprotein drug efflux that confers resistance to drugs.…”