Backbone Degradable N-(2-Hydroxypropyl)methacrylamide Copolymer Conjugates with Gemcitabine and Paclitaxel: Impact of Molecular Weight on Activity toward Human Ovarian Carcinoma Xenografts

Abstract

Degradable diblock and multiblock (tetrablock and hexablock) N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-gemcitabine (GEM) and -paclitaxel (PTX) conjugates were synthesized by reversible addition-fragmentation chain-transter (RAFT) copolymerization followed by click reaction for preclinical investigation. The aim was to validate the hypothesis that long-circulating conjugates are needed to generate a sustained concentration gradient between vasculature and a solid tumor and result in significant anticancer effect. To evaluate the impact of molecular weight of the conjugates on treatment efficacy, diblock, tetrablock, and hexablock GEM and PTX conjugates were administered intravenously to nude mice bearing A2780 human ovarian xenografts. For GEM conjugates, triple doses with dosage 5 mg/kg were given on days 0, 7, and 14 (q7dx3), whereas a single dose regime with 20 mg/kg was applied on day 0 for PTX conjugates treatment. The most effective conjugates for each monotherapy were the diblock ones, 2P-GEM and 2P-PTX (Mw ≈ 100 kDa). Increasing the Mw to 200 or 300 kDa resulted in decrease of activity most probably due to changes in the conformation of the macromolecule because of interaction of hydrophobic residues at side chain termini and formation of "unimer micelles". In addition to monotherapy, a sequential combination treatment of diblock PTX conjugate followed by GEM conjugate (2P-PTX/2P-GEM) was also performed, which showed the best tumor growth inhibition due to synergistic effect: complete remission was achieved after the first treatment cycle. However, because of low dose applied, tumor recurrence was observed 2 weeks after cease of treatment. To assess optimal route of administration, intraperitoneal (i.p.) application of 2P-GEM, 2P-PTX, and their combination was examined. The fact that the highest anticancer efficiency was achieved with diblock conjugates that can be synthesized in one scalable step bodes well for the translation into clinics.

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

“…Using this strategy, a series of drug (gemcitabine (GEM) and paclitaxel (PTX)) conjugates were synthesized and evaluated in a preclinical tumor model bearing s.c. human ovarian A2780 xenografts [51]. Each group consisted of 5 female mice.…”

A Nanostrategy for Efficient Imaging‐Guided Antitumor Therapy through a Stimuli‐Responsive Branched Polymeric Prodrug

“…Recently, biodegradable HPMA polymeric conjugates with MWs of 100–300 kDa have been prepared with enhanced accumulation in tumors and increased therapeutic indexes, while they still maintain excellent biosafety . In our previous studies, biodegradable high MWs branched pHPMA polymers have been demonstrated with high accumulation in tumors and excellent biosafety .…”

The Development of a Macromolecular Analgesic for Arthritic Pain

“…To ensure proper renal clearance, any necessary M w increase beyond the 45 kDa glomerular filtration threshold may justify the use of biodegradable polymeric carriers (e.g., dextran, hyaluronic acid, etc.) or the use of hybrid carriers, − which may partially degrade and yield HPMA copolymers of much shorter length. Future therapeutic efficacy studies should also include repeated dosing regimens, the data from which could further demonstrate the superior efficacy and safety of the macromolecular prodrug design as a new class of analgesic.…”