Targeted polymeric therapeutic nanoparticles: design, development and clinical translation

Abstract

Polymeric materials have been used in a range of pharmaceutical and biotechnology products for more than 40 years. These materials have evolved from their earlier use as biodegradable products such as resorbable sutures, orthopaedic implants, macroscale and microscale drug delivery systems such as microparticles and wafers used as controlled drug release depots, to multifunctional nanoparticles (NPs) capable of targeting, and controlled release of therapeutic and diagnostic agents. These newer generations of targeted and controlled release polymeric NPs are now engineered to navigate the complex in vivo environment, and incorporate functionalities for achieving target specificity, control of drug concentration and exposure kinetics at the tissue, cell, and subcellular levels. Indeed this optimization of drug pharmacology as aided by careful design of multifunctional NPs can lead to improved drug safety and efficacy, and may be complimentary to drug enhancements that are traditionally achieved by medicinal chemistry. In this regard, polymeric NPs have the potential to result in a highly differentiated new class of therapeutics, distinct from the original active drugs used in their composition, and distinct from first generation NPs that largely facilitated drug formulation. A greater flexibility in the design of drug molecules themselves may also be facilitated following their incorporation into NPs, as drug properties (solubility, metabolism, plasma binding, biodistribution, target tissue accumulation) will no longer be constrained to the same extent by drug chemical composition, but also become in-part the function of the physicochemical properties of the NP. The combination of optimally designed drugs with optimally engineered polymeric NPs opens up the possibility of improved clinical outcomes that may not be achievable with the administration of drugs in their conventional form. In this critical review, we aim to provide insights into the design and development of targeted polymeric NPs and to highlight the challenges associated with the engineering of this novel class of therapeutics, including considerations of NP design optimization, development and biophysicochemical properties. Additionally, we highlight some recent examples from the literature, which demonstrate current trends and novel concepts in both the design and utility of targeted polymeric NPs (444 references).

Synthesis, Functionalization, and Design of Magnetic Nanoparticles for Theranostic Applications

“…[475] Although this approach has been proposed about 40 years ago, [476] ligand-decorated nanoparticles have recently paved their way to clinical trials. [477] Increase in affinity and its consequent specific cell binding is achieved by NPs equipped with targeting species which are complementary to unique receptors on target cells. Accessibility of the specific antigen on targeted cells for an appropriate binding to ligand-decorated NPs is crucial during this approach.…”

“…[489] Since the first approved antibody in 1986, [490] muromonab-CD3, numerous antibody platforms such as chimeric, murine, and humanized antibodies have been developed with more than 30 types of them being approved for clinical uses. [477] The inherent antibodies ability to distinguish between healthy and cancerous cells and even among cancer cell types fairly motivates their use for active targeting. [18] Anti-HER2 Mab (also called Herceptin or trastuzumab), [491] rimuximab (Rituxan), [492] Anti-CD3 Mab, [493] Anti CEA Mab, [494] and huA33 mAB [495] are of some mostly used anitbodies for decorating nanoparticles in treating cancers.…”

“…[530] In fact, aptamers are artificially selected sequences of short single-stranded nucleic acids such as DNA, RNA or modified oligonucleotides which can fold into numerous unique 3D conformations. [477,531] These conformations which originate from intramolecular Watson-Crick interactions, [462] have extremely high affinity in binding small and large biochemical targets. [532] However, finding the appropriate sequence able to participate in ligand binding is akin to finding a needle in a haystack.…”

“…[462,477] In recent years, the utility of aptamers has been enhanced through many techniques, in particular the one in which SELEX is performed with complex mixtures of biological materials and cell-SELEX. [498,533] By this technique aptamers which recognize specific cell lines are generated within an in vitro selection performed with whole live cells.…”

“…[565] Although RGD peptides offer some advantages, nonspecific adhesion is still a remaining challenge since α v β 3 integrin receptors are also expressed on normal tissue and non-cancerous inflamed tissues. [477] …”