Co-Entrapment of Sorafenib and Cisplatin Drugs and iRGD Tumour Homing Peptide by Poly[ε-caprolactone-co-(12-hydroxystearate)] Copolymer

The drug-loaded nanocarriers have overcome various challenges compared with the pure chemotherapeutic drug, such as limited bioavailability, multiple drug resistance, poor patient compliance, and adverse drug reactions, offering advantages such as protection from degradation in the blood stream, better drug solubility, and improved drug stability. One promising group of controlled and targeted drug delivery systems is polymer-based nanoparticles that can sustain the release of the active agent by diffusion and their degradation. Sorafenib is the only drug that can prolong the life of patients suffering from hepatocellular carcinoma. Cisplatin remains one of the most widely used broad-spectrum anticancer drugs for the treatment of a variety of solid tumours. Nanoformulations can exert a synergistic effect by entrapping two drugs with different modes of action, such as sorafenib and cisplatin. In our study, polymeric nanoparticles were prepared with a good production yield by an improved double emulsion solvent evaporation method using the copolymer of 12-hydroxystearic acid with ε-caprolactone (12CL), a biocatalytically synthesised biocompatible and biodegradable carrier, for the co-entrapment of sorafenib and cisplatin in nanotherapeutics. A bovine serum albumin (BSA) model compound was used to increase the cisplatin incorporation; then, it was successfully substituted by a iRGD tumour penetrating peptide that might provide a targeting function of the nanoparticles.

Neutrophils mediated multistage nanoparticle delivery for prompting tumor photothermal therapy

Background Neutrophil-based drug delivery system possesses excellent advantages in targeting at tumour because neutrophils are easily recruited by chemotactic factor in tumor microenvironment. Herein, we developed a novel tactic of multistage neutrophils-based nanoparticle delivery system for promoting photothermal therapy (PTT) of lung cancer. Results Au nanorod (AuNR) was successfully modified with bovine serum albumin (AuNRB) and further conjugated with RGD (AuNRBR), followed by neutrophil internalisation to obtain neutrophils-based delivery system (AuNRBR/N). The engineered neutrophils efficiently migrated across the epithelial cells due to inflammatory signal. They exhibited better toxicity against Lewis cells with laser irradiation in vitro. Moreover, AuNRBR/N showed significantly more targetability to tumour tissue compared with cell carrier-free AuNRBR, as demonstrated in Lewis tumour-bearing mice. The enhanced tumour homing efficiency of AuNRBR/N together with subsequently released AuNRBR from the neutrophils was favourable for further deep tissue diffusion and contributed to the inhibition of the tumour growth in PTT and improved survival rate (over 120 days). Conclusions Overall results illustrated that the design of cell-based nanoparticle delivery system for PTT of cancer is promising.

Safety and Homing of Human Dental Pulp Stromal Cells in Head and Neck Cancer

Background: Head and neck cancer (HNC) is one of the most common cancers, associated with a huge mortality and morbidity. In order to improve patient outcomes, more efficient and targeted therapies are essential. Bone marrow-derived mesenchymal stromal cells (BM-MSCs) express tumour homing capacity, which could be exploited to target anti-cancer drug delivery to the tumour region and reduce adverse side-effects. Nevertheless, dental pulp stromal cells (DPSCs), an MSC-like population present in teeth, could offer important clinical benefits because of their easy isolation and superior proliferation compared to BM-MSCs. Therefore, we aimed to elucidate the tumour homing and safe usage of DPSCs to treat HNC. Methods: The in vivo survival as well as the effect of intratumourally administered DPSCs on tumour aggressiveness was tested in a HNC xenograft mouse model by using bioluminescence imaging (BLI), (immuno)histology and qRT-PCR. Furthermore, the in vitro and in vivo tumour homing capacity of DPSCs towards a HNC cell line were evaluated by a transwell migration assay and BLI, respectively. Results: Intratumourally injected DPSCs survived for at least two weeks in the tumour micro-environment and had no significant influence on tumour morphology, growth, angiogenesis and epithelial-to-mesenchymal transition. In addition, DPSCs migrated towards tumour cells in vitro, which could not be confirmed after their in vivo intravenous, intraperitoneal or peritumoural injection under the tested experimental conditions. Conclusions: Our research suggests that intratumourally delivered DPSCs might be used as safe factories for the continuous delivery of anti-cancer drugs in HNC. Nevertheless, further optimization as well as efficacy studies are necessary to understand and improve in vivo tumour homing and determine the optimal experimental set-up of stem cell-based cancer therapies, including dosing and timing.

Neutrophils Mediated Multistage Nanoparticle Delivery for Prompting Tumor Photothermal Therapy

Background : Neutrophil-based drug delivery system possesses excellent advantages in targeting at tumour because neutrophils are easily recruited by chemotactic factor in tumor microenvironment. Herein, we developed a novel tactic of multistage neutrophils-based nanoparticle delivery system for promoting photothermal therapy (PTT) of lung cancer. Results: Au nanorod (AuNR) was successfully modified with bovine serum albumin (AuNRB) and further conjugated with RGD (AuNRBR), followed by neutrophil internalisation to obtain neutrophils-based delivery system (AuNRBR/N). The engineered neutrophils efficiently migrated across the epithelial cells due to inflammatory signal. They exhibited better toxicity against Lewis cells with laser irradiation in vitro . Moreover, AuNRBR/N showed significantly more targetability to tumour tissue compared with cell carrier-free AuNRBR, as demonstrated in Lewis tumour-bearing mice. The enhanced tumour homing efficiency of AuNRBR/N together with subsequently released AuNRBR from the neutrophils was favourable for further deep tissue diffusion and contributed to the inhibition of the tumour growth in PTT and improved survival rate (over 120 days). Conclusions: Overall results illustrated that the design of cell-based nanoparticle delivery system for PTT of cancer is promising.

The Synthesis of Peptide-Conjugated Poly(2-Ethyl-2-Oxazoline)-bpoly(L-Lactide) (PEtOx-B-PLA) Polymeric Systems Through the Combination of Controlled Polymerization Techniques and Click Reactions

To optimize the therapeutic effect of pharmaceutical agents, drug delivery systems tailored from FDA-approved polymers like poly(L-lactide) (PLA) is an effective strategy. Because of their hydrophobic character, these systems greatly suffer from reduced circulation time thus, amphiphilic block copolymers became favourable to overcome this limitation. Of them, poly(oxazoline)-b-poly(L-lactide) are of choice as poly(oxazoline) (PEtOx) is compatibile, biodegradable, while exhibiting minimum cytotoxicity. To tailor selective drug targeting drug delivery systems, whereby their selectivity for tumour tissues is maximised, these polymers should be decorated with so-called tumour-homing agents, such as antibodies, peptides and so forth. To this respect, we designed a new block copolymer, allyl-poly(2-ethyl-2-oxazoline)-b-poly(L-lactide) allyl-(PEtOx-b-PLA) and its subsequent conjugation to tumour-homing peptides, peptide-18 and peptide-563 at the terminal position. In this manuscript, we report our synthetic route to obtain this building block and its conjugation to tumour-homing agents.

The Synthesis of Peptide-Conjugated Poly(2-Ethyl-2-Oxazoline)-bpoly(L-Lactide) (PEtOx-B-PLA) Polymeric Systems Through the Combination of Controlled Polymerization Techniques and Click Reactions

To optimize the therapeutic effect of pharmaceutical agents, drug delivery systems tailored from FDA-approved polymers like poly(L-lactide) (PLA) is an effective strategy. Because of their hydrophobic character, these systems greatly suffer from reduced circulation time thus, amphiphilic block copolymers became favourable to overcome this limitation. Of them, poly(oxazoline)-b-poly(L-lactide) are of choice as poly(oxazoline) (PEtOx) is compatibile, biodegradable, while exhibiting minimum cytotoxicity. To tailor selective drug targeting drug delivery systems, whereby their selectivity for tumour tissues is maximised, these polymers should be decorated with so-called tumour-homing agents, such as antibodies, peptides and so forth. To this respect, we designed a new block copolymer, allyl-poly(2-ethyl-2-oxazoline)-b-poly(L-lactide) allyl-(PEtOx-b-PLA) and its subsequent conjugation to tumour-homing peptides, peptide-18 and peptide-563 at the terminal position. In this manuscript, we report our synthetic route to obtain this building block and its conjugation to tumour-homing agents.

Neutrophils Mediated Multistage Nanoparticle Delivery for Prompting Tumor Photothermal Therapy

Background Neutrophil-based drug delivery system possesses excellent advantages in targeting at tumour because neutrophils are easily recruited by chemotactic factor in tumor microenvironment. Herein, we developed a novel tactic of multistage neutrophils-based nanoparticle delivery system for promoting photothermal therapy (PTT) of lung cancer. Results Au nanorod (AuNR) was successfully modified with bovine serum albumin (AuNRB) and further conjugated with RGD (AuNRBR), followed by neutrophil internalisation to obtain neutrophils-based delivery system (AuNRBR/N). The engineered neutrophils efficiently migrated across the epithelial cells due to inflammatory signal. They exhibited better toxicity against Lewis cells with laser irradiation in vitro. Moreover, AuNRBR/N showed significantly more targetability to tumour tissue compared with cell carrier-free AuNRBR, as demonstrated in Lewis tumour-bearing mice. The enhanced tumour homing efficiency of AuNRBR/N together with subsequently released AuNRBR from the neutrophils was favourable for further deep tissue diffusion and contributed to the inhibition of the tumour growth in PTT and improved survival rate (over 120 days). Conclusions Overall results illustrated that the design of cell-based nanoparticle delivery system for PTT of cancer is promising.

Visualizing tumour self-homing with magnetic particle imaging

Due to their innate tumour homing capabilities, in recent years, CTCs have been engineered to express therapeutic genes for targeted treatment of primary and metastatic lesions. Additionally, previous studies have incorporated optical or PET imaging reporter genes to enable noninvasive monitoring of therapeutic CTCs in preclinical tumour models. Here, we demonstrate for the first time, the ability of magnetic particle imaging (MPI) to sensitively detect systemically administered iron-labeled CTCs and to visualize tumour self-homing in a murine model of human breast cancer.

Mesenchymal Stem Cell Expressing TRAIL as Targeted Therapy against Sensitised Tumour

Tapping into the ability of engineered mesenchymal stem cells (MSCs) to mobilise into the tumour has expanded the scope of cancer treatment. Engineered MSCs expressing tumour necrosis factor (TNF)-related apoptosis inducing ligand (MSC-TRAIL) could serve as a platform for an efficient and targeted form of therapy. However, the presence of cancer stem cells (CSCs) that are resistant to TRAIL and apoptosis may represent a challenge for effective treatment. Nonetheless, with the discovery of small molecular inhibitors that could target CSCs and tumour signalling pathways, a higher efficacy of MSC-TRAIL mediated tumour inhibition can be achieved. This might pave the way for a more effective form of combined therapy, which leads to a better treatment outcome. In this review, we first discuss the tumour-homing capacity of MSCs, its effect in tumour tropism, the different approach behind genetically-engineered MSCs, and the efficacy and safety of each agent delivered by these MSCs. Then, we focus on how sensitisation of CSCs and tumours using small molecular inhibitors can increase the effect of these cells to either TRAIL or MSC-TRAIL mediated inhibition. In the conclusion, we address a few questions and safety concerns regarding the utilization of engineered MSCs for future treatment in patients.