Ligand-targeted particulate nanomedicines undergoing clinical evaluation: current status.

Since the introduction of Doxil® on the market nearly 20years ago, a number of nanomedicines have become part of treatment regimens in the clinic. With the exception of antibody-drug conjugates, these nanomedicines are all devoid of targeting ligands and rely solely on their physicochemical properties and the (patho)physiological processes in the body for their biodistribution and targeting capability. At the same time, many preclinical studies have reported on nanomedicines exposing targeting ligands, or ligand-targeted nanomedicines, yet none of these have been approved at this moment. In the present review, we provide a concise overview of 13 ligand-targeted particulate nanomedicines (ligand-targeted PNMs) that have progressed into clinical trials. The progress of each ligand-targeted PNM is discussed based on available (pre)clinical data. Main conclusions of these analyses are that (a) ligand-targeted PNMs have proven to be safe and efficacious in preclinical models; (b) the vast majority of ligand-targeted PNMs is generated for the treatment of cancer; (c) contribution of targeting ligands to the PNM efficacy is not unambiguously proven; and (d) targeting ligands do not cause localization of the PNM within the target tissue, but rather provide benefits in terms of target cell internalization and target tissue retention once the PNM has arrived at the target site. Increased understanding of the in vivo fate and interactions of the ligand-targeted PNMs with proteins and cells in the human body is mandatory to rationally advance the clinical translation of ligand-targeted PNMs. Future perspectives for ligand-targeted PNM approaches include the delivery of drugs that are unable or inefficient in passing cellular membranes, treatment of drug resistant tumors, targeting of the tumor blood supply, the generation of targeted vaccines and nanomedicines that are able to cross the blood-brain barrier.

van der Meel R ，Vehmeijer LJ ，Kok RJ ，Storm G ，van Gaal EV ... -  《-》

Role of integrated cancer nanomedicine in overcoming drug resistance.

Cancer remains a major killer of mankind. Failure of conventional chemotherapy has resulted in recurrence and development of virulent multi drug resistant (MDR) phenotypes adding to the complexity and diversity of this deadly disease. Apart from displaying classical physiological abnormalities and aberrant blood flow behavior, MDR cancers exhibit several distinctive features such as higher apoptotic threshold, aerobic glycolysis, regions of hypoxia, and elevated activity of drug-efflux transporters. MDR transporters play a pivotal role in protecting the cancer stem cells (CSCs) from chemotherapy. It is speculated that CSCs are instrumental in reviving tumors after the chemo and radiotherapy. In this regard, multifunctional nanoparticles that can integrate various key components such as drugs, genes, imaging agents and targeting ligands using unique delivery platforms would be more efficient in treating MDR cancers. This review presents some of the important principles involved in development of MDR and novel methods of treating cancers using multifunctional-targeted nanoparticles. Illustrative examples of nanoparticles engineered for drug/gene combination delivery and stimuli responsive nanoparticle systems for cancer therapy are also discussed.

Iyer AK ，Singh A ，Ganta S ，Amiji MM ... -  《-》

Lipid-polymer hybrid nanoparticles as a new generation therapeutic delivery platform: a review.

Hadinoto K ，Sundaresan A ，Cheow WS 《-》

Carbon nanotubes for delivery of small molecule drugs.

In the realm of drug delivery, carbon nanotubes (CNTs) have gained tremendous attention as promising nanocarriers, owing to their distinct characteristics, such as high surface area, enhanced cellular uptake and the possibility to be easily conjugated with many therapeutics, including both small molecules and biologics, displaying superior efficacy, enhanced specificity and diminished side effects. While most CNT-based drug delivery system (DDS) had been engineered to combat cancers, there are also emerging reports that employ CNTs as either the main carrier or adjunct material for the delivery of various non-anticancer drugs. In this review, the delivery of small molecule drugs is expounded, with special attention paid to the current progress of in vitro and in vivo research involving CNT-based DDSs, before finally concluding with some consideration on inevitable complications that hamper successful disease intervention with CNTs.

Wong BS ，Yoong SL ，Jagusiak A ，Panczyk T ，Ho HK ，Ang WH ，Pastorin G ... -  《-》

Transferrin-conjugated nanoparticles of poly(lactide)-D-alpha-tocopheryl polyethylene glycol succinate diblock copolymer for targeted drug delivery across the blood-brain barrier.

We developed in this research a nanoparticle system for targeted drug delivery across the blood-brain barrier (BBB), which consists of the transferrin (Tf) conjugated nanoparticles of poly(lactide)-D-alpha-Tocopheryl polyethylene glycol succinate (PLA-TPGS) diblock copolymer. The NPs were prepared by the nanoprecipitation method and characterized for their various physicochemical and pharmaceutical properties. Cellular uptake and cytotoxicity of the Tf-conjugated PLA-TPGS NPs formulation of coumarin 6 as a model imaging agent or Docetaxel as a model drug were investigated in close comparison with those for the PLGA NPs formulation, the bare PLA-TPGS NPs formulation as well as with the clinical Taxotere. The Tf-conjugated PLA-TPGS NPs formulation demonstrated great advantages over the other two NPs formulations and the original imaging/therapeutic agents. IC50 data showed that the Tf-conjugated PLA-TPGS NPs formulation of Docetaxel could be 23.4%, 16.9% and 229% more efficient than the PLGA NPs, the PLA-TPGS NPs formulations and Taxotere after 24 h treatment, respectively. Moreover, our preliminary ex vivo biodistribution investigation demonstrated that although not as satisfactory, the Tf-conjugated PLA-TPGS NPs formulation could be able to deliver imaging/therapeutic agents across the BBB.

Gan CW ，Feng SS 《-》