In general, native drug molecules do not fulfill these requirements. On the other hand, conventional therapeutic agents mediate their pharmacological effect in a dissolved state and a dynamic conversion from stable drug colloids to solubilized drug molecules is required. 18 Hypothetical nanopharmaceuticals with the highest imaginable drug to carrier ratio and most simple synthesis would be composed of drug molecules only which assemble into NPs themselves. Moreover, the aim of a high drug to carrier ratio corresponds to the modern concepts of “atom economy” and “multifunctional efficiency” in the context of NPs. 17 High drug loading is generally a desired parameter of drug delivery systems in order to minimize exposure of patients to nanocarrier material and reduce possible adverse reactions. However, delivering small molecule drugs by encapsulation into MOF pores is not trivial and depending on the used drug and MOF, the drug content varies significantly. As MOFs span a rich chemical space of about 70 000 reported structures 10 with varying degrees of porosity 8, 11 and tailorable sizes, 12 they are mainly explored for catalysis, 13 gas storage, 14 separation, 15 sensing, 16 and drug delivery 3, 17 applications. 9 Several MOFs utilize polydentate carboxylic acid linkers and their coordinative interactions with metal ions to obtain defined crystalline structures. Recently, highly regular coordination polymers such as metal-organic frameworks 8 (MOFs) have emerged as an additional class of nanomaterials. 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. 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. As a consequence, high doses are required for efficient tumor treatment but the severe dose-limiting off-target effects determine a narrow therapeutic window and impair patient benefits in the clinical practice. 1 Conventional chemotherapy often suffers from unfavorable pharmacokinetics, limited tumor accumulation, and systemic toxicity. NP drug delivery systems are therefore being investigated to overcome the poor selectivity and major side effects frequently associated with chemotherapy. Nanoparticles (NPs) which are small enough to circulate in the 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. Pharmacokinetic properties are inherent characteristics of drug molecules that cannot be changed without derivatization. This study illustrates the development and characterization of metal-drug coordination NPs with high drug content and variable external functionalizations. Attaching folate or transferrin ligands to the polymer layer enhances NP uptake into target receptor positive KB and L1210 cells. 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. The NP core is stabilized against serum with a shell of a polymerized oligoamine-modified trimethoxysilane derivative (TMSP). Since the NP core is generated from drug molecules as essential units, it features a very high drug content of almost 80%. The metal-drug NP core is assembled in a bottom-up approach by coordinative interactions between zirconium (IV) ions and PMX molecules. This study presents the development of a multilayer PMX NP system where each layer serves a distinct purpose.
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. Such nanomaterials exhibit a high material economy due to high drug contents and minor amounts of inactive additives. Selected drug molecules with Lewis base functions can be assembled into coordinative nanoparticles (NPs) by linking them with suitable metal ions.
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