Core‐Shell Functionalized Zirconium‐Pemetrexed Coordination Nanoparticles as Carriers with a High Drug Content

Abstract

Selected drug molecules with Lewis base functions can be assembled into coordinative nanoparticles (NPs) by linking them with suitable metal ions. Such nanomaterials exhibit a high material economy due to high drug contents and minor amounts of inactive additives. The antifolate pemetrexed (PMX) which is used for the treatment of lung cancers contains two carboxy functions that are able to undergo coordinative binding of metal ions. This study presents the development of a multilayer PMX NP system where each layer serves a distinct purpose. The metal-drug NP core is assembled in a bottom-up approach by coordinative interactions between zirconium (IV) ions and PMX molecules. Since the NP core is generated from drug molecules as essential units, it features a very high drug content of almost 80%. The NP core is stabilized against serum with a shell of a polymerized oligoamine-modified trimethoxysilane derivative (TMSP). As external layer, a polyglutamate-block-polysarcosine-N 3 (pGlu-b-pSar) coating mediates efficient colloidal stabilization and enables introduction of targeting functionalities by click chemistry. Attaching folate or transferrin ligands to the polymer layer enhances NP uptake into target receptor positive KB and L1210 cells. This study illustrates the development and characterization of metal-drug coordination NPs with high drug content and variable external functionalizations.bloodstream and carry cargo molecules are attractive materials for the utilization as drug containers since their pharmacokinetic properties can be tuned without affecting the pharmacodynamics of the drug. NP drug delivery systems are therefore being investigated to overcome the poor selectivity and major side effects frequently associated with chemotherapy. [1] Conventional chemotherapy often suffers from unfavorable pharmacokinetics, limited tumor accumulation, and systemic toxicity. As a consequence, high doses are required for efficient tumor treatment but the severe doselimiting off-target effects determine a narrow therapeutic window and impair patient benefits in the clinical practice. [2] Recent approaches in nanotechnology work toward ameliorating the situation by developing chemotherapeutic NP formulations aimed at increasing drug selectivity toward neoplastic tissues by employing active and passive targeting strategies of single or combination therapies [3] and enhancing therapeutic indices. [4] At present, about 40 nanomedicines, [5] for instance liposomal doxorubicin [6] and iron-oxide NP formulations, [7] are used for a variety of indications. Recently, highly regular coordination polymers such as metal-organic frameworks [8] (MOFs) have emerged as an additional class of nanomaterials. [9] Several MOFs utilize polydentate carboxylic acid linkers and their

Targeting Cancer Chemotherapy Resistance by Precision Medicine-Driven Nanoparticle-Formulated Cisplatin

“…The conjugation of cisplatin induced the self-assembly of the hydrophilic pSar 160 - b -pGlu­(ONa) 31 , yielding polymeric micelles with a diameter of Ø ∼ 28 nm and a narrow PDI of 0.15 (Figure b). Our NP size was reported to be small enough to ensure bloodstream circulation while still allowing passive EPR targeting even of poorly permeable tumors and seems optimal for endocytosis-mediated transport. − To avoid artifacts caused by the fixation procedures of conventional transmission electron microscopy (TEM), we used cryo-EM to confirm shape, size, and homogeneity of our NP Cis (Figure c). The neutral ξ-potential of −5.89 ± 6.48 mV accounts for the steric shielding by the pSar layer (Figure d).…”

“…The product was dried in vacuo (91.1 mg, 82%), and the absence of unconjugated dye was verified by HFIP-GPC. The synthesis of pSar- b -pGlu was performed as described previously by Steinborn et al . Similarly, block lengths of 160 for pSar and 31 for pGlu were used for NP Cis formation.…”

Photocleavable core cross-linked polymeric micelles of polypept(o)ides and ruthenium(ii) complexes

“…Neopentylamine (NPA)-initiated poly (g-tert-butyl-L-glutamic acid)-block-poly(sarcosine) (pGlu(OtBu)b-pSar) was prepared via sequential NCA polymerization, as reported previously. 50 Briefly, 394.5 mg (1.72 mmol; 30 eq.) of g-tert-butyl-L-glutamic acid (Glu(OtBu)) NCA were weighed into a pre-died Schlenk-flask, dissolved in anhydrous DMF (freshly amine-purified by freeze-thaw cycles) at a concentration of 200 g L À1 , cooled to 0 1C, and NPA (5.0 mg; 57.4 mmol; 1.0 eq.)…”

Chitin/Metal‐Organic Framework Composites as Wide‐Range Adsorbent

“…Therefore, in this work we have combined a macro‐ and mesoporous chitin (CH) [12–15] biopolymer with the MOF‐808 microporous metal‐organic framework (MOF) [16,25,17–24] sorbent to create a porous composite with multiple porosities and chemical functionalities [28–30] . CH is the second most abundant natural polymer [31,32] .…”