Overcoming the Challenges in the Effective Delivery of Chemotherapies to CNS Solid Tumors

Abstract

Locoregional therapies, such as surgery and intratumoral chemotherapy, do not effectively treat infiltrative primary CNS solid tumors and multifocal metastatic solid tumor disease of the CNS. It also remains a challenge to treat such CNS malignant solid tumor disease with systemic chemotherapies, although these lipid-soluble small-molecule drugs demonstrate potent cytotoxicity in vitro. Even in the setting of a ‘normalized’ tumor microenvironment, small-molecule drugs do not accumulate to effective concentrations in the vast majority of tumor cells, which is due to the fact that small-molecule drugs have short blood half-lives. It has been recently shown that drug-conjugated spherical lipid-insoluble nanoparticles within the 7–10 nm size range can deliver therapeutic concentrations of drug fraction directly into individual tumor cells following systemic administration, since these functionalized particles maintain peak blood concentrations for several hours and are smaller than the physiologic upper limit of pore size in the VEGF-derived blood capillaries of solid tumors, which is approximately 12 nm. In this article, the physiologic and ultrastructural basis of this novel translational approach for the treatment of CNS, as well as non-CNS, solid cancers is reviewed.

Conserved molecular mechanisms underlying the effects of small molecule xenobiotic chemotherapeutics on cells

“…This is the case of those within the overall lipophilicity range of cyclophosphamide/ifosfamide (Log OWPC-to-vdWD ratio, 0.14 nm -1 ; vdWD, 0.73 nm) (34,42,43) which are of larger size, and carmustine (Log OWPC-to-vdWD ratio, 1.41 nm -1 ; vdWD, 0.67 nm) (44), which is more lipophilic (44), for which there is a greater tendency to associate with and perturb CM phospholipids and the potential for a 1ary indirect pressuromodulation-mediated secondary increase in very high molecular weight (MW) protein transcription (17), while such small molecule xenobiotics of lipophilic character may only achieve intra-cellular levels at significant extracellular concentrations (45), which makes the more lipophilic xenobiotics of this category marginal chemoxenobiotics for effective transvascular delivery into solid tumor tissue (3)(4)(5)(6)(7) .…”

“…Thus, such xenobiotic chemotherapies have shown the potential to be uniformly cytotoxic to tumor cells, via effects in both nuclear and mitochondrial compartments in the setting of an actively maintained concentration gradient in vitro, particularly synergistically (28,29). Therefore, in order to demonstrate similar effectiveness in the clinical setting, such small molecule xenobiotics, as well as others discussed herein, must be made to first and foremost selectively accumulate to effective concentrations within tumor tissue, which can only be accomplished upon labile linking to optimally-sized, and designed, nanoparticles within the 8-to 9-nm-size range delivered transvascularly (3)(4)(5)(6)(7), to ensure uniform cytotoxicity to all tumor tissue cells and minimal risk for subsequent neoplastic transformation of tumor-associated cells including tumor stem cells.…”

“…The insight to be gained is to be applicable for the selection of existing chemoxenobiotics most synergistic in cytotoxic effects and the development of more effective existing chemotherapy regimens utilizing small molecule chemoxenobiotics (14,15). This knowledge is applicable for the discovery of alternative xenobiotics with chemotherapeutic potential to overcome chemotherapeutic resistance (16), as well as for the design and development of next generation biocompatible optimally sized drug carriers free from intravascular protein interactions, for effective transvascular delivery into solid tumor tissue cells (3)(4)(5)(6)(7).…”

“…For this reason, a better understanding of the modes and character underlying molecular cellular interactions is necessary, particularly for the purposes of improving the tumor tissue selectiveness of enhanced permeation and retention (EPR)-based chemotherapy (2), which has a prolonged blood half-life but is non-selective for solid tumor foci. Along these lines, there has been relatively recent translational advancement towards the development of optimally sized dendrimer nanoparticle-based small molecule chemotherapy at ~9 nm (H D ) (3-7), which selectively delivers small molecule chemoxenobiotics into solid malignancies at effective concentrations without systemic toxicity (4,8). As such, with optimally sized dendrimer nanoparticle-based small molecule chemotherapy, there is the potential for complete tumor regression (3,9) in lieu of the possibility for the development of drug resistance phenotypes (10,11) and therapy-related malignancies (12) or myelodysplastic syndromes (13).…”

“…During the discovery and developmental stages, the testing of small molecule xenobiotics occurs at several levels: i) at the naked target, on chromatin or on a protein receptor/enzyme in isolation, which provides information on relative binding affinities for intra-cellular proteins; ii) at the cellular level in vitro, which provides information on the inhibitory concentrations needed to achieve tumor cell death and the overexpression status of induced pro-or anti-apoptotic protein forms, but does not take into consideration cell membrane (CM) phospholipid or CM protein receptor interactions, the most common level of interaction for secondary intra-cellular effects of non-permeable small molecule xenobiotics, either due to molecular size restriction to permeation or charge restriction to permeation (4,8); iii) at the systemic level in vivo, which gives an idea of the dosing range necessary to achieve a chemotherapeutic effect and tumor regression, and in the case of more lipophilic chemoxenobiotics, the dosing required to overcome serum protein binding, this being the primary limitation to achieving effective transvascular delivery and intra-tumoral concentrations in cases of free small molecule xenobiotics, not linked to optimally sized nanoparticles (3)(4)(5)(6)(7).…”