Cancer Drug Delivery: Considerations in the Rational Design of Nanosized Bioconjugates

Abstract

In order to efficiently deliver anticancer agents to tumors, biocompatible nanoparticles or bioconjugates, including antibody–drug conjugates (ADCs), have recently been designed, synthesized, and tested, some even in clinical trials. Controlled delivery can be enhanced by changing specific design characteristics of the bioconjugate such as its size, the nature of the payload, and the surface features. The delivery of macromolecular drugs to cancers largely relies on the leaky nature of the tumor vasculature compared with healthy vessels in normal organs. When administered intravenously, macromolecular bioconjugates and nanosized agents tend to circulate for prolonged times, unless they are small enough to be excreted by the kidney or stealthy enough to evade the macrophage phagocytic system (MPS), formerly the reticulo-endothelial system (RES). Therefore, macromolecular bioconjugates and nanosized agents with long circulation times leak preferentially into tumor tissue through permeable tumor vessels and are then retained in the tumor bed due to reduced lymphatic drainage. This process is known as the enhanced permeability and retention (EPR) effect. However, success of cancer drug delivery only relying on the EPR effect is still limited. To cure cancer patients, further improvement of drug delivery is required by both designing superior agents and enhancing EPR effects. In this Review, we describe the basis of macromolecular or nanosized bioconjugate delivery into cancer tissue and discuss current diagnostic methods for evaluating leakiness of the tumor vasculature. Then, we discuss methods to augment conventional “permeability and retention” effects for macromolecular or nanosized bioconjugates in cancer tissue.

RuIII Complexes for Anticancer Therapy: The Importance of Being Nucleolipidic

“…[139][140][141][142] Flexibility in obtaining tailor-made nanoparticles with specific features (e.g., molecular weight, number and types of at-tached drugs, targeting moieties and even bioresponsive components) [143] makes such systems suitable drug-delivery vehicles. Generally, these masses are removed by surgery, but this approach is not suitable for small or hidden tumours.…”

Chemical Synthesis and Medicinal Applications of Glycoporphyrins

“…It involves the administration of a PS agent either intravenously or topologically to the body which can accumulate in cancer tissue largely due to the enhanced permeability and retention (EPR) effect [9][10][11] . These PS agents can be activated with specific wavelengths to produce reactive oxygen species (ROS), often singlet oxygen, which in turn induces irreversible cancer tissue damage.…”

“…Thus, with several modifications, the Eschenmoser sulfide contraction/iminoester cyclization method [154] was incorporated in the assembly of the four monocyclic pyrrole precursors (11,12,14,15) to yield 19. Establishing protecting groups X at C-7 and C-13 allowed for double elimination yielding the tetrahydroporphyrin and upon oxidation gave the chromophore 21 (Scheme 3) [153] .…”

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“…Challenges of the tumor micro environment and the imperatives of radioactive gold nanoparticles in tumor therapy From the point of administration of drugs in human patients, their transport, movement, accumulation in tumor targets, their degradation and their ultimate excretion from the body-are all dictated by a very complex equation comprising of blood flow rate and vascular morphology [11][12][13][14][15][16][17][18][19]. As the injected dose, traversers through the point of delivery into the body, the kinetics, fate and the accumulation of drugs are dictated by a number of factors including the spatial geometry, diameter, length of blood vessels and number of blood vessels.…”

“…In a physical sense, such effects make tumor cells significantly more porous than normal cells thus allowing passage of oxygen, liposomes, nanoparticles, macromolecular drugs molecules, nutrients, and other solutes from the bloodstream to the tumor tissues, through the enhanced permeability and retention (EPR) effect [11][12][13][14][15][16][17][18][19]. The EPR effects also contribute to significant inefficacies in tumor therapy due to uneven accumulation of drugs within the tumor as well as fast clearance of accumulated drugs before exerting therapeutic effects within the tumor capsule.…”