Over the past few decades, numerous polymer drug carrier systems are designed and synthesized, and their properties are evaluated. Many of these systems are based on water‐soluble polymer carriers of low‐molecular‐weight drugs and compounds, e.g., cytostatic agents, anti‐inflammatory drugs, or multidrug resistance inhibitors, all covalently bound to a carrier by a biodegradable spacer that enables controlled release of the active molecule to achieve the desired pharmacological effect. Among others, the synthetic polymer carriers based on N‐(2‐hydroxypropyl) methacrylamide (HPMA) copolymers are some of the most promising carriers for this purpose. This review focuses on advances in the development of HPMA copolymer carriers and their conjugates with anticancer drugs, with triggered drug activation in tumor tissue and especially in tumor cells. Specifically, this review highlights the improvements in polymer drug carrier design with respect to the structure of a spacer to influence controlled drug release and activation, and its impact on the drug pharmacokinetics, enhanced tumor uptake, cellular trafficking, and in vivo antitumor activity.
International audienceThe development of flexible drug delivery systems that can be tuned as a function of the drug to bedelivered and of the target disease is crucial in modern medicine. For this aim, novel amphiphilic poly-(e-caprolactone)-g-poly(ethylene glycol) (PCL-g-PEG) copolymers with well-controlled design weresynthesized by thiol–yne photochemistry. The grafting density and the copolymer amphiphilicity wereeasily controlled via the reaction parameters: concentration, reaction time, PEG length and the molarratio between PCL and PEG or the photoinitiator in the reaction mixture. The self-assembling behaviorof the copolymers was studied and a correlation between the composition of PCL-g-PEG and thenanoaggregate diameter sizes (28 to 73 nm) and critical aggregation concentrations (1.1 to 4.3 mg L1)was found. The influence of copolymer amphiphilicity on the drug loading was evaluated with variousdrugs including anticancer drugs (paclitaxel, ABT-199), drugs to overcome multidrug resistance incancer cells (curcumin, elacridar), an anti-inflammatory drug (dexamethasone) and an antibacterial drug(clofazimine). Finally, the influence of amphiphilicity on curcumin release and toxicity towards MCF-7cancer cell lines was studied. The impact of the grafting density, PEG length and the overall EG/CL ratiois discussed in detail. Curcumin loaded PCL-g-PEG with lower EG/CL ratios and shorter PEG chainsshowed higher toxicity compared to their more hydrophilic counterparts
Many conjugates of water-soluble polymers with biologically active molecules were developed during the last two decades. Although, therapeutic effects of these conjugates are affected by the properties of carriers, the properties of the attached drugs appear more important than the same carrier polymer in this case. Pirarubicin (THP), a tetrahydropyranyl derivative of doxorubicin (DOX), demonstrated more rapid cellular internalization and potent cytotoxicity than DOX. Here, we conjugated the THP or DOX to N-(2-hydroxypropyl)methacrylamide copolymer via a hydrazone bond. The polymeric prodrug conjugates, P-THP and P-DOX, respectively, had comparable hydrodynamic sizes and drug loading. Compared with P-DOX, P-THP showed approximately 10 times greater cellular uptake during a 240 min incubation and a cytotoxicity that was more than 10 times higher during a 72-h incubation. A marginal difference was seen in P-THP and P-DOX accumulation in the liver and kidney at 6 h after drug administration, but no significant difference occurred in the tumor drug concentration during 6-24 h after drug administration. Antitumor activity against xenograft human pancreatic tumor (SUIT2) in mice was greater for P-THP than for P-DOX. To sum up, the present study compared the biological behavior of two different drugs, each attached to an N-(2-hydroxypropyl)methacrylamide copolymer carrier, with regard to their uptake by tumor cells, body distribution, accumulation in tumors, cytotoxicity, and antitumor activity in vitro and in vivo. No differences in the tumor cell uptake of the polymer-drug conjugates, P-THP and P-DOX, were observed. In contrast, the intracellular uptake of free THP liberated from the P-THP was 25-30 times higher than that of DOX liberated from P-DOX. This finding indicates that proper selection of the carrier, and especially conjugated active pharmaceutical ingredient (API) are most critical for anticancer activity of the polymer-drug conjugates. THP, in this respect, was found to be a more preferable API for polymer conjugation than DOX. Hence the treatment based on enhanced permeability and retention (EPR) effect that targets more selectively to solid tumors can be best achieved with THP, although both polymer conjugates of DOX and THP exhibited the EPR effects and drug release profiles in acidic pH similarly.
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