Facile Route to Targeted, Biodegradable Polymeric Prodrugs for the Delivery of Combination Therapy for Malaria

Abstract

A facile synthetic methodology has been developed to prepare multifaceted polymeric prodrugs that are targeted, biodegradable, and nontoxic, and used for the delivery of combination therapy. This is the first instance of the delivery of the WHO recommended antimalarial combination of lumefantrine (LUM, drug 1) and artemether (AM, drug 2) via a polymeric prodrug. To achieve this, reversible addition-fragmentation chain transfer (RAFT)-mediated polymerization of N-vinylpyrrolidone (NVP) was conducted using a hydroxy-functional RAFT agent, and the resulting polymer was used as the macroinitiator in the ring-opening polymerization (ROP) of α-allylvalerolactone (AVL) to synthesize the biodegradable block copolymer of poly­(N-vinylpyrrolidone) and poly­(α-allylvalerolactone) (PVP-b-PAVL). The ω-end thiol group of PVP was protected using 2,2′-pyridyldisulfide prior to the ROP, and was conveniently used to bioconjugate a peptidic targeting ligand. To attach LUM, the allyl groups of PVP-b-PAVL underwent oxidation to introduce carboxylic acid groups, which were then esterified with ethylene glycol vinyl ether. Finally, LUM was conjugated to the block copolymer via an acid-labile acetal linkage in a “click”-type reaction, and AM was entrapped within the hydrophobic core of the self-assembled aggregates to render biodegradable multidrug-loaded micelles with targeting ability for combination therapy.

A Water‐Soluble Polymer‐Lumefantrine Conjugate for the Intravenous Treatment of Severe Malaria

“…The recent attempt at developing a combination therapy that included a polymeric drug of lumefantrine was unsuccessful as the in vitro antiplasmodial activity was about a thousand times less than the combination of the free artemether and lumefantrine. [ 11,24 ]…”

“…Recently, a polymeric prodrug of lumefantrine was synthesized and used to encapsulate artemether in an unsuccessful attempt to demonstrate a potential ACT nanomedicine. [ 24 ] There was also no indication of the degree of aqueous solubility achieved from conjugating lumefantrine to the water‐soluble block copolymer of poly(N‐vinylpyrrolidone) and poly( α ‐allylvalerolactone), and the nanoaggregate combination showed no antiplasmodial activity in vitro, which was attributed to slow aggregate disassembly. We report the development of a polymer‐lumefantrine conjugate and demonstrate its therapeutic potential by intravenous administration in a clinically relevant aqueous formulation to mice infected with the P. falciparum human parasite.…”

Polymeric Nanoparticle Based Diagnosis and Nanomedicine for Treatment and Development of Vaccines for Cerebral Malaria: A Review on Recent Advancement

“…Finally, this assembly entrapped the second drug molecule (i.e., artemether), and the resulting formulation was used for combination therapy for malaria. Although these formulations showed less release of drugs as compared to the free delivery of lumefantrine and artemether in combination mode, the toxicity was found to be decreased by encapsulating both the drugs in the polymeric micelles …”

“…Although these formulations showed less release of drugs as compared to the free delivery of lumefantrine and artemether in combination mode, the toxicity was found to be decreased by encapsulating both the drugs in the polymeric micelles. 133 3.5. Nanogel Based Malaria Medicine.…”

Dealing with the complexity of conjugated and self‐assembled polymer‐nanostructures using field‐flow fractionation

“…Most SAPs possess amphiphilic properties, and thus, inherently susceptible to phase segregation to produce unique self-assembled and membranous nanostructures, some of them with cargo encapsulation and release capabilities. 27,28,29 onto the polymer chain via a disulfide bond to give a self-aggregating pDHPMA-DOX-SS-mPEG molecule. 27 The recent upsurge in smart 35 Reprinted with permission from ref.…”