Sequential combination therapy of ovarian cancer with degradable N -(2-hydroxypropyl)methacrylamide copolymer paclitaxel and gemcitabine conjugates

Abstract

For rapid and effective clinical translation, polymer-based anticancer therapeutics need long circulating conjugates that produce a sustained concentration gradient between the vasculature and solid tumor. To this end, we designed second-generation backbone-degradable diblock N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer carriers and evaluated sequential combination therapy of HPMA copolymer-paclitaxel and HPMA copolymer-gemcitabine conjugates against A2780 human ovarian carcinoma xenografts. First, extensive in vitro assessment of administration sequence impact on cell cycle, viability, apoptosis, migration, and invasion revealed that treatment with paclitaxel conjugate followed by gemcitabine conjugate was the most effective scheduling strategy. Second, in an in vivo comparison with first-generation (nondegradable, molecular weight below the renal threshold) conjugates and free drugs, the second-generation degradable highmolecular weight conjugates showed distinct advantages, such as favorable pharmacokinetics (three-to five-times half-life compared with the first generation), dramatically enhanced inhibition of tumor growth (complete tumor regression) by paclitaxel and gemcitabine conjugate combination, and absence of adverse effects. In addition, multimodality imaging studies of dual-labeled model conjugates confirmed the efficacy of second-generation conjugates by visualizing more than five-times enhanced tumor accumulation, rapid conjugate internalization, and effective intracellular release of payload. Taken together, the results indicate that the second-generation degradable HPMA copolymer carrier can provide an ideal platform for the delivery of a range of antitumor compounds, which makes it one of the most attractive candidates for potential clinical application. macromolecular therapeutics | EPR effect | dual-isotope label I n the past decades, numerous polymers have been developed as drug carriers, but so far only a few progressed to clinical evaluation, such as N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-drug conjugates (1-3). Results from clinical trials with first-generation HPMA conjugates (4-6) indicated a significant decrease of adverse effects compared with small-molecule drugs; however, the therapeutic efficacy did not match the data in preclinical animal studies. The most likely reason is that the molecular weight (Mw) of first-generation HPMA copolymer conjugates used in the trials was only 25 kDa, not large enough to ensure sufficient circulation time in the human body and sufficient extravasation of the conjugates at the tumor by enhanced permeability and retention (EPR) effect (7). Consequently, tumors were not exposed to effective drug concentrations. For prolonged plasma circulation and enhanced tumor accumulation, it is imperative to use polymeric carriers with increased Mw, which makes high-Mw biodegradable polymeric conjugates the most attractive candidates for future clinical applications (8, 9). Thus, we designed second-generation HPMA copolymer carriers that contain e...

The light at the end of the tunnel—second generation HPMA conjugates for cancer treatment

“…It was demonstrated that the combination of PTX and GEM is schedule-dependent; treatment with PTX followed by GEM has the strongest synergism [60] (Fig. 6.I).…”

“…Combination of gemcitabine with paclitaxel was evaluated on nu/nu mice bearing s.c. A2780 human ovarian carcinoma xenografts [60]. Notably, long retention time of drugs in the circulation is crucial to cell-cycle-specific drugs such as PTX and GEM, which can exert effective actions on cells only in a specific phase of cell cycle.…”

Enzyme/pH-sensitive dendritic polymer-DOX conjugate for cancer treatment

“…poly[N-(2-hydroxypropyl) methacrylamide] (poly-HPMA) has served as a favorable drug delivery carrier owing to its high solubility in water, biocompatibility, and non-immunogenicity [16][17][18][19]. In the early stage in the development of HPMA drug conjugates, HPMA with a high molecular weight (HMW) was directly utilized to conjugate drugs [20].…”

A smart polymeric platform for multistage nucleus-targeted anticancer drug delivery

“…The sub-units possess a biforked structure with one end conjugated with H1 peptide, and the other end conjugated with a novel fusion targeting peptide (R8NLS) composed of NLS (PKKKRKV) and cell penetrating peptide (octaarginine or R8). The sub-units were conjugated to HPMA polymers via a glycylphenylalanylleucylglycine (GFLG) linker that is lysosomally enzymatic degradable [23,24]. Thus, once the system is internalized into the cell, the sub-units could be unleashed for nuclear transport of the therapeutic peptides.…”