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Pentamidine (PTM) is an aromatic diamidine approved for the treatment of parasitic infections that has been recently proposed for possible repositioning as an anticancer drug. To this aim, efforts have been made to improve its therapeutic efficacy and reduce associated adverse effects through both covalent derivatization and association with nanocarriers. To efficiently encapsulate PTM into biocompatible nanoparticles and to enhance its selectivity toward cancer cells, a squalene (SQ) derivative (1,1',2-tris-norsqualenoic acid, SQ-COOH) was selected to prepare PTM-loaded nanocarriers. Indeed, SQ and its derivatives self-assemble into nanoparticles in aqueous media. Furthermore, SQ-bioconjugates strongly interact with low-density lipoproteins (LDL), thus favoring preferential accumulation in cells overexpressing the LDL receptor (LDLR). We report here the preparation of nanocarriers by ion-pairing between the negatively charged SQ-COOH and the positively charged PTM free base (PTM-B), which allowed the covalent grafting of SQ to PTM to be avoided. The nanoparticles were characterized (mean size < 200 nm and zeta potential < -20 mV for SQ-COOH/PTM-B 3:1 molar ratio) and molecular modelling studies of the SQ-COOH/PTM-B interaction confirmed the nanocarrier stability. Finally, the ability to indirectly target LDLR-overexpressing cancer cells was evaluated by in vitro cell viability assays and confirmed by LDLR silencing, serum privation and simvastatin treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The aim of the present study is to take advantage of the unique property of polyisoprenoid chains to adopt a compact molecular conformation and to use these natural and biocompatible lipids as nanocarriers of drugs to deliver siRNA. A new chemical strategy is applied here to conjugate squalene (SQ) and solanesol (SOLA) to siRNA consisting of an activated variant of the azide-alkyne Huisgen cycloaddition also known as copper-free (Cu-free) click chemistry. We conjugated siRNA against TMPRSS2-ERG, a fusion oncogene found in more than 50% of prostate cancers to SQ or SOLA. First, several parameters such as molar ratio, solvents, temperature, incubation time, and the annealing schedule between both siRNA strands were investigated to bioconjugate the SQ or SOLA via Cu-free click chemistry. The best parameters of the new bioconjugation approach allowed us to (i) increase the synthesis yield up to 95%, (ii) avoid the formation of byproducts during the synthesis, and (iii) improve the reproducibility of the bioconjugation. Then, the biological activity of the resulting nanoparticles was assessed. In vitro, all four formulations were able to decrease the corresponding oncogene and oncoprotein expression. In vivo, only two of the four nanoformulations showed anti-neoplastic activity that seems to be tightly related to their dissimilar biodistribution behavior. In conclusion, we performed a new approach easily transposable for pharmaceutical development to synthesize siRNA-SQ and siRNA-SOLA and to obtain efficient siRNA-nanoparticles. The robustness of the process could be extended to several other polyterpenes and likely applied to other siRNA targeting genes whose overexpression results in the development of cancers or other genetic diseases.

In this work we prepared and characterized two liposomal formulations of a semisynthetic nitric oxide (NO)-releasing doxorubicin (Dox), called nitrooxy-Dox (NitDox), which we previously demonstrated to be cytotoxic in Dox-resistant human colon cancer cells. Liposomes with 38.2% (Lip A) and 19.1% (Lip B) cholesterol were synthesized: both formulations had similar size and zeta potential values and caused the same intracellular distribution of free NitDox, but Lip B accumulated and released NitDox more efficiently. In Dox-resistant human colon cancer cells, Lip A and Lip B exhibited a more favorable kinetics of drug uptake and NO release, and a stronger cytotoxicity than Dox and free NitDox. While Caelyx, one of the liposomal Dox formulations approved for breast and ovary tumors treatment, was ineffective in Dox-resistant breast/ovary cancer cells, Lip B, and to a lesser extent Lip A, still exerted a significant cytotoxicity in these cells. This event was accompanied in parallel by a higher release of NO, which caused nitration of P-glycoprotein (Pgp) and multidrug resistance related protein 1 (MRP1), two transporters involved in Dox efflux, and impaired their pump activity. By doing so, the efflux kinetics of Dox after treatment with Lip B was markedly slowed down and the intracellular accumulation of Dox was increased in breast and ovary drug-resistant cells. We propose these liposomal formulations of NitDox as new tools with a specific indication for tumors overexpressing Pgp and MRP1.

Hyaluronic acid (HA) is a naturally-occurring glycosaminoglycan and a major component of the extracellular matrix. Low levels of the hyaluronic acid receptor CD44 are found on the surface of epithelial, hematopoietic, and neuronal cells; it is overexpressed in many cancer cells, and in particular in tumor-initiating cells. HA has recently attracted considerable interest in the field of developing drug delivery systems, having been used, as such or encapsulated in different types of nanoassembly, as ligand to prepare nano-platforms for actively targeting drugs, genes, and diagnostic agents. This review describes recent progress made with the several chemical strategies adopted to synthesize conjugates and prepare novel delivery systems with improved behaviors.

Antibody-delivered drugs and toxins are poised to become important classes of cancer therapeutics. These biopharmaceuticals have potential in this field, as they can selectively direct highly potent cytotoxic agents to cancer cells that present tumor-associated surface markers, thereby minimizing systemic toxicity. The activity of some conjugates is of particular interest receiving increasing attention, thanks to very promising clinical trial results in hematologic cancers. Over twenty antibody-drug conjugates and eight immunotoxins in clinical trials as well as some recently approved drugs, support the maturity of this approach. This review focuses on recent advances in the development of these two classes of biopharmaceuticals: conventional toxins and anticancer drugs, together with their mechanisms of action. The processes of conjugation and purification, as reported in the literature and in several patents, are discussed and the most relevant results in clinical trials are listed. Innovative technologies and preliminary results on novel drugs and toxins, as reported in the literature and in recently-published patents (up to February 2013) are lastly examined.

Importance of the Field: Taxanes have received considerable attention owing to their significant activity against a variety of tumors. Nevertheless, many different approaches have been developed to improve their safety profile and water solubility, in terms of both dosing schedules and delivery strategies., Areas Covered in This Review: Among the different taxane delivery systems, macromolecule conjugates have been widely explored; this review collects and summarizes such systems from reports after 1990. Natural and synthetic polymers, proteins and polysaccharides have been covalently coupled with taxanes; immunoconjugates have also been developed for targeted delivery. In-depth descriptions, from synthesis to preclinical or clinical data, are given., What the Reader Will Gain: The choice of macromolecule, the spacer, the chemistry of the linkage with taxane, as well as other cytotoxic drugs, are key points to obtain effective conjugates with higher activity than that of the free drug, reducing side effects. Critical evaluation of the different approaches may help in comprehending and comparing the results and may elucidate the role of individual components., Take Home Message: Taxane covalently-bound to macromolecules shows advanced properties, and although only one compound is in advanced clinical trials, this area deserves attention and seems a promising route to achieve effective new anticancer compounds.