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Melanoma is the most aggressive and metastasis-prone form of skin cancer. Conventional therapies include chemotherapeutic agents, either as small molecules or carried by FDA-approved nanostructures. However, systemic toxicity and side effects still remain as major drawbacks. With the advancement of nanomedicine, new delivery strategies emerge at a regular pace, aiming to overcome these challenges. Stimulus-responsive drug delivery systems might considerably reduce systemic toxicity and side-effects by limiting drug release to the affected area. Herein, we report the development of paclitaxel-loaded lipid-coated manganese ferrite magnetic nanoparticles (PTX-LMNP) as magnetosomes synthetic analogs, envisaging the combined chemo-magnetic hyperthermia treatment of melanoma. PTX-LMNP physicochemical properties were verified, including their shape, size, crystallinity, FTIR spectrum, magnetization profile, and temperature profile under magnetic hyperthermia (MHT). Their diffusion in porcine ear skin (a model for human skin) was investigated after intradermal administration via fluorescence microscopy. Cumulative PTX release kinetics under different temperatures, either preceded or not by MHT, were assessed. Intrinsic cytotoxicity against B16F10 cells was determined via neutral red uptake assay after 48 h of incubation (long-term assay), as well as B16F10 cells viability after 1 h of incubation (short-term assay), followed by MHT. PTX-LMNP-mediated MHT triggers PTX release, allowing its thermal-modulated local delivery to diseased sites, within short timeframes. Moreover, half-maximal PTX inhibitory concentration (IC50) could be significantly reduced relatively to free PTX (142,500×) and Taxol® (340×). Therefore, the dual chemo-MHT therapy mediated by intratumorally injected PTX-LMNP stands out as a promising alternative to efficiently deliver PTX to melanoma cells, consequently reducing systemic side effects commonly associated with conventional chemotherapies.

Doxorubicin (DOX) is a chemotherapeutic agent commonly used for the treatment of solid tumors. However, the cardiotoxicity associated with its prolonged use prevents further adherence and therapeutic efficacy. By encapsulating DOX within a PEGylated liposome, Doxil® considerably decreased DOX cardiotoxicity. By using thermally sensitive lysolipids in its bilayer composition, ThermoDox® implemented a heat-induced controlled release of DOX. However, both ThermoDox® and Doxil® rely on their passive retention in tumors, depending on their half-lives in blood. Moreover, ThermoDox® ordinarily depend on invasive radiofrequency-generating metallic probes for local heating. In this study, we prepare, characterize, and evaluate the antitumoral capabilities of DOX-loaded folate-targeted PEGylated magnetoliposomes (DFPML). Unlike ThermoDox®, DOX delivery via DFPML is mediated by the heat released through dynamic hysteresis losses from magnetothermal converting systems composed by MnFe2O4 nanoparticles (NPs) under AC magnetic field excitation—a non-invasive technique designated magnetic hyperthermia (MHT). Moreover, DFPML dismisses the use of thermally sensitive lysolipids, allowing the use of simpler and cheaper alternative lipids. MnFe2O4 NPs and DFPML are fully characterized in terms of their size, morphology, polydispersion, magnetic, and magnetothermal properties. About 50% of the DOX load is released from DFPML after 30 min under MHT conditions. Being folate-targeted, in vitro DFPML antitumoral activity is higher (IC50 ≈ 1 μg/ml) for folate receptor-overexpressing B16F10 murine melanoma cells, compared to MCF7 human breast adenocarcinoma cells (IC50 ≈ 4 μg/ml). Taken together, our results indicate that DFPML are strong candidates for folate-targeted anticancer therapies based on DOX controlled release.

Guided tissue regeneration (GTR) is a dentistry technique based on the use of polymeric biomembranes as physical barriers for selective cell exclusion, directing the growth of gingival tissue, bone tissue, and periodontal ligaments in a region previously affected by periodontitis. Postoperative pain and microbial infection constitute, however, two major challenges to be tackled right after implantation. To address these challenges, we prepared and characterized eight chitosan/hyaluronic acid/glycerol (CS/HA/GL) bioresorbable membranes embedded with lidocaine- and chloramphenicol-loaded polycaprolactone nanoparticles (LDNP and CHNP, respectively), combining the local anesthetic effects of lidocaine with the antibacterial effects of chloramphenicol. The formulations were prepared with varying amounts of CS, HA, GL, LDNP, and CHNP. As a plasticizing agent, GL could modulate the samples mechanical properties such as thickness, morphology, tensile strength, elongation at break, as well as swelling and degradation in simulated saliva. Two samples exhibited greater resistance to biodegradation and were selected for further studies. Their drug release profiles indicated that LDNP and CHNP first detach from the membrane matrix, and a zeroth order drug release kinetics from the detached NPs dominates the overall process thereafter, with lidocaine being released 3 times faster than chloramphenicol, in a controlled and sustained rate over time. Drug encapsulation efficiency was such that optimal samples exhibited bactericidal activity (inhibition halos) against gram-positive S. aureus and gram-negative A. actinomycetemcomitans strains similar to that observed for free chloramphenicol. Finally, one of these samples showed no intrinsic toxicity against healthy mammalian model cells (99% viability for the unloaded membrane; 80% viability for the fully LDNP- and CHNP-loaded membrane), and may now be further optimized as a drug-eluting biomembrane with potential for GTR.

Inducing immunogenic cell death (ICD) during cancer therapy is a major challenge that might significantly improve patient survival. The purpose of this study was to develop a theranostic nanocarrier, capable both of conveying a cytotoxic thermal dose when mediating photothermal therapy (PTT) after its intravenous delivery, and of consequently inducing ICD, improving survival. The nanocarrier consists of red blood cell membranes (RBCm) embedding the near-infrared dye IR-780 (IR) and camouflaging Mn-ferrite nanoparticles (RBCm-IR-Mn). The RBCm-IR-Mn nanocarriers were characterized by size, morphology, surface charge, magnetic, photophysical, and photothermal properties. Their photothermal conversion efficiency was found to be size- and concentration-dependent. Late apoptosis was observed as the cell death mechanism for PTT. Calreticulin and HMGB1 protein levels increased for in vitro PTT with temperature around 55 °C (ablative regime) but not for 44 °C (hyperthermia), suggesting ICD elicitation under ablation. RBCm-IR-Mn were then intravenously administered in sarcoma S180-bearing Swiss mice, and in vivo ablative PTT was performed five days later. Tumor volumes were monitored for the subsequent 120 days. RBCm-IR-Mn-mediated PTT promoted tumor regression in 11/12 animals, with an overall survival rate of 85% (11/13). Our results demonstrate that the RBCm-IR-Mn nanocarriers are great candidates for PTT-induced cancer immunotherapy.