Exploring nanocarriers as innovative materials for advanced drug delivery strategies in onco-immunotherapies.

In recent years, Onco-immunotherapies (OIMTs) have been shown to be a potential therapy option for cancer. Several immunotherapies have received regulatory approval, while many others are now undergoing clinical testing or are in the early stages of development. Despite this progress, a large number of challenges to the broad use of immunotherapies to treat cancer persists. To make immunotherapy more useful as a treatment while reducing its potentially harmful side effects, we need to know more about how to improve response rates to different types of immunotherapies. Nanocarriers (NCs) have the potential to harness immunotherapies efficiently, enhance the efficiency of these treatments, and reduce the severe adverse reactions that are associated with them. This article discusses the necessity to incorporate nanomedicines in OIMTs and the challenges we confront with current anti-OIMT approaches. In addition, it examines the most important considerations for building nanomedicines for OIMT, which may improve upon current immunotherapy methods. Finally, it highlights the applications and future scenarios of using nanotechnology.

Dacarbazine-primed carbon quantum dots coated with breast cancer cell-derived exosomes for improved breast cancer therapy.

Imprecise targeting of chemotherapeutic drugs often leads to severe toxicity during breast cancer therapy. To address this issue, we have devised a strategy to load dacarbazine (DC) into fucose-based carbon quantum dots (CQDs), which are subsequently coated with exosomes (Ex-DC@CQDs) derived from breast cancer cells. Nanoparticle tracking analysis and western blotting revealed that Ex-DC@CQDs retained the structural and functional characteristics of exosomes. We found that exosomes facilitated the transport of DC@CQDs to cancer cells via heparan sulfate proteoglycan (HSPG) receptors, followed by an augmented depolarization of the mitochondrial membrane potential, ROS generation, and induction of apoptosis leading to cell death. In vivo imaging and pharmacokinetic studies demonstrated enhanced antitumor targeting and efficacy compared to free DC which we attribute to an improved pharmacokinetic profile, a greater tumor accumulation via exosome-mediated- HSPG receptor-driven cell uptake, and sustained release of the Ex-DC@CQDs. Our findings may pave the way for the further development of biologically sourced nanocarriers for breast cancer targeting.

Surface-Modified Lyotropic Crystalline Nanoconstructs Bearing Doxorubicin and Buparvaquone Target Sigma Receptors through pH-Sensitive Charge Conversion to Improve Breast Cancer Therapy.

In the current study, we aimed to develop lyotropic crystalline nanoconstructs (LCNs) based on poly(l-glutamic acid) (PLG) with a two-tier strategy. The first objective was to confer pH-responsive charge conversion properties to facilitate the delivery of both doxorubicin (DOX) and buparvaquone (BPQ) in combination (B + D@LCNs) to harness their synergistic effects. The second goal was to achieve targeted delivery to sigma receptors within the tumor tissues. To achieve this, we designed a pH-responsive charge conversion system using a polymer consisting of poly(ethylenimine), poly(l-lysine), and poly(l-glutamic acid) (PLG), which was then covalently coupled with methoxybenzamide (MBA) for potential sigma receptor targeting. The resulting B + D@LCNs were further modified by surface functionalization with PLG-MBA to confer both sigma receptor targeting and pH-responsive charge conversion properties. Our observations indicated that at physiological pH 7.4, P/B + D-MBA@LCNs exhibited a negative charge, while under acidic conditions (pH 5.5, characteristic of the tumor microenvironment), they acquired a positive charge. The particle size of P/B + D-MBA@LCNs was determined to be 168.23 ± 2.66 nm at pH 7.4 and 201.23 ± 1.46 nm at pH 5.5. The crystalline structure of the LCNs was confirmed through small-angle X-ray scattering (SAXS) diffraction patterns. Receptor-mediated endocytosis, facilitated by P/B + D-MBA@LCNs, was confirmed using confocal laser scanning microscopy and flow cytometry. The P/B + D-MBA@LCNs formulation demonstrated a higher rate of G2/M phase arrest (55.20%) compared to free B + D (37.50%) and induced mitochondrial depolarization (59.39%) to a greater extent than P/B + D@LCNs (45.66%). Pharmacokinetic analysis revealed significantly improved area under the curve (AUC) values for both DOX and BPQ when administered as P/B + D-MBA@LCNs, along with enhanced tumor localization. Tumor regression studies exhibited a substantial reduction in tumor size, with P/B + D-MBA@LCNs leading to 3.2- and 1.27-fold reductions compared to B + D and nontargeted P/B + D@LCNs groups, respectively. In summary, this two-tier strategy demonstrates substantial promise for the delivery of a drug combination through the prototype formulation. It offers a potential chemotherapeutic option by minimizing toxic effects on healthy cells while maximizing therapeutic efficacy.

Immobilized doxorubicin and ribociclib carbamate linkers encaged in surface modified cubosomes spatially target tumor reductive environment to enhance antitumor efficacy.

In the present investigation, we have strategically synthesized Glutathione (GSH) stimuli-sensitive analogues using carbamate linkers (CL) of DOX (DOX-CL) and RB (RB-CL) which were then anchored to gold nanoparticles (Au-DOX-CL, Au-RB-CL) using mPEG as a spacer. It was observed that carbamate linkage (CL) with four carbon spacer is critical, to position the terminal thiol group, to access the carbamate group efficiently to achieve GSH-assisted release of DOX and RB in tumor-specific environment. When assessed for GSH reductase activity in MDA-MB 231 cell lines, Au-DOX-CL and Au-RB-CL showed nearly 4.18 and 3.13 fold higher GSH reductive activity as compared to the control group respectively. To achieve spatial tumor targeting with a high payload of DOX and RB, Au-DOX-CL and Au-RB-CL were encapsulated in the cell-penetrating peptide (CPP) modified liquid crystalline cubosomes i.e. CPP-Cu(Au@CL-DR). After internalization, the prototype nanocarriers release respective drugs at a precise GSH concentration inside the tumor tissues, amplifying drug concentration to a tune of five-fold. The drug concentrations remain within the therapeutic window for 72 h with a significant reduction of RB (7.8-fold) and DOX (6-fold) concentrations in vital organs, rendering reduced toxicity and improved survival. Overall, this constitutes a promising chemotherapeutic strategy against cancer and its potential application in the offing.

Surface modification strategies in translocating nano-vesicles across different barriers and the role of bio-vesicles in improving anticancer therapy.

Nanovesicles and bio-vesicles (BVs) have emerged as promising tools to achieve targeted cancer therapy due to their ability to overcome many of the key challenges currently being faced with conventional chemotherapy. These challenges include the diverse and often complex pathophysiology involving the progression of cancer, as well as the various biological barriers that circumvent therapeutic molecules reaching their target site in optimum concentration. The scientific evidence suggests that surface-functionalized nanovesicles and BVs camouflaged nano-carriers (NCs) both can bypass the established biological barriers and facilitate fourth-generation targeting for the improved regimen of treatment. In this review, we intend to emphasize the role of surface-functionalized nanovesicles and BVs camouflaged NCs through various approaches that lead to an improved internalization to achieve improved and targeted oncotherapy. We have explored various strategies that have been employed to surface-functionalize and biologically modify these vesicles, including the use of biomolecule functionalized target ligands such as peptides, antibodies, and aptamers, as well as the targeting of specific receptors on cancer cells. Further, the utility of BVs, which are made from the membranes of cells such as mesenchymal stem cells (MSCs), white blood cells (WBCs), red blood cells (RBCs), platelets (PLTs) as well as cancer cells also been investigated. Lastly, we have discussed the translational challenges and limitations that these NCs can encounter and still need to be overcome in order to fully realize the potential of nanovesicles and BVs for targeted cancer therapy. The fundamental challenges that currently prevent successful cancer therapy and the necessity of novel delivery systems are in the offing.

Synergistic delivery of Imatinib through multifunctional nano-crystalline capsules, in response to redox environment for improved breast cancer therapy.

Chondroitin anchored crystalline nano-capsules bearing Imatinib (IMT), and simvastatin (SMV) was developed using Poly (L-lactic acid) (PLLA) by two-step method, i.e., firstly, by synthesizing chondroitin (CSA) anchored simvastatin (SMV) using cystamine as a spacer (SMV-SS-CSA) for disulfide triggered glutathione (GSH) sensitive release and secondly, by developing phenyl boronic ester grafted Pluronic F68 (PEPF) for H2O2 responsive release. By combining these conjugates, we have prepared crystalline nano-capsules (CNs) for preferential targeting of CD44 receptors. The developed CNs were spherical when characterized through SEM, TEM, and AFM for surface morphology, while changes in particle size and crystalline structure were confirmed through Quasi-Elastic light scattering (QELS) and Wide Angle X-ray Scattering (WAXS). The enhanced cellular uptake was noted in chondroitin-modified nano-capsules IMT/SMV-SS-CSA@CNs compared to unmodified nano-capsules IMT+SMV@CNs. IMT/SMV-SS-CSA@CNs displayed significantly higher G2/M phase arrest (76.9%) than unmodified nano-capsules. The prototype formulation (IMT/SMV-SS-CSA@CNs) showed an overall improved pharmacokinetic profile in terms of both half-life and AUC0-α. When tested in the 4T1 subcutaneously injected tumor-bearing Balb/c mice model, the tumor growth inhibition rate of IMT/SMV-SS-CSA@CNs was significantly higher (91%) than the IMT+SMV combination. Overall, the findings suggest that the proposed dual responsive chondroitin-modified drug delivery could have a step forward in achieving spatial and temporal targeting at the tumor site.

Self-Assembled Redox-Sensitive Polymeric Nanostructures Facilitate the Intracellular Delivery of Paclitaxel for Improved Breast Cancer Therapy.

A two-tier approach has been proposed for targeted and synergistic combination therapy against metastatic breast cancer. First, it comprises the development of a paclitaxel (PX)-loaded redox-sensitive self-assembled micellar system using betulinic acid-disulfide-d-α-tocopheryl poly(ethylene glycol) succinate (BA-Cys-T) through carbonyl diimidazole (CDI) coupling chemistry. Second, hyaluronic acid is anchored to TPGS (HA-Cys-T) chemically through a cystamine spacer to achieve CD44 receptor-mediated targeting. We have established that there is significant synergy between PX and BA with a combination index of 0.27 at a molar ratio of 1:5. An integrated system comprising both BA-Cys-T and HA-Cys-T (PX/BA-Cys-T-HA) exhibited significantly higher uptake than PX/BA-Cys-T, indicating preferential CD44-mediated uptake along with the rapid release of drugs in response to higher glutathione concentrations. Significantly higher apoptosis (42.89%) was observed with PX/BA-Cys-T-HA than those with BA-Cys-T (12.78%) and PX/BA-Cys-T (33.38%). In addition, PX/BA-Cys-T-HA showed remarkable enhancement in the cell cycle arrest, improved depolarization of the mitochondrial membrane potential, and induced excessive generation of ROS when tested in the MDA-MB-231 cell line. An in vivo administration of targeted micelles showed improved pharmacokinetic parameters and significant tumor growth inhibition in 4T1-induced tumor-bearing BALB/c mice. Overall, the study indicates a potential role of PX/BA-Cys-T-HA in achieving both temporal and spatial targeting against metastatic breast cancer.

Recent updates on innovative approaches to overcome drug resistance for better outcomes in cancer.

The multi-dimensional challenge of drug resistance is one of the pivotal hindrances for cancer chemotherapy. A reductive approach to define and distinguish the main aspects of drug resistance, such as tumor growth kinetics about tumor micro-environment (tumor multifariousness), therapeutic pressure, physical barricades, irreversible genetic mutation, as well as role of the immune system, are the main causes of failure in cancer therapy are presented systematically. We are focusing on general approaches to reduce drug resistance: earlier diagnosis of tumors allowing for cancer halting; dynamic surveillance throughout treatment; the adding of new therapeutic strategies and improve pharmacodynamics precepts resulting in profound effects; and identification of cancerous cells repositories using high-throughput monitoring, as well as the interoperability of clinical- gene mapping statics are described in detail. These strategies could be potentially constructed for any tumor at any precise moment and used to guide therapy selection. Chemotherapeutic agents results in mild improved survival in clinical trials owing to several pathophysiologic obstacles, such as intra-tumoral dispersion, invasion & intra-cellular transportation. This review highlights recent advancements in developing new therapeutic innovations to combat drug resistance in cancer therapy by overcoming various barricades in the tumor microenvironment.

Amalgamated Microneedle Array Bearing Ribociclib-Loaded Transfersomes Eradicates Breast Cancer via CD44 Targeting.

HR+/HER2- metastatic breast cancer (MBC) is one of the most common and life-threatening conditions diagnosed in women. The endocrine therapy using an orally active CDK4/6 inhibitor, ribociclib (RB), is the most intriguing approach for treating HR+/HER2- MBC. However, the repeated three to six cycles of multiple dosing and non-targeted distribution of RB led to severe neutropenia; hepatobiliary, gastrointestinal, and renal toxicities, and QT interval prolongation. Here, a novel organic solvent-free HA-PVA-PVP (hyaluronic acid-polyvinyl alcohol-polyvinyl pyrrolidone) composed of a microneedle (MN) array is formulated to deliver RB, integrated with amphiphilic conjugated polymer (HA-GMS)-anchored ultradeformable transfersomes. This unique MN array efficiently crafts microchannels in the skin, allowing HA-RB-Ts to internalize into the tumor cells through lymphatic and systemic absorption and interact with CD44 both spatially and temporally with an amplification of drug release time up to 6-folds. The pharmacokinetic and tissue distribution studies portray drug concentrations within the therapeutic window as long as 48 h, facilitating thrice-a-week frequency with the lower dose, and rule out severe toxicities, with a significant reduction in 8.3-fold RB concentration in vital organs that ultimately enhances the survival rate. Thus, the novel MN system pursues a unique embeddable feature and offers an effective, self-administrable, biodegradable, and chronic treatment option for patients requiring long-term cancer treatments.

Development of putrescine anchored nano-crystalsomes bearing doxorubicin and oleanolic acid: deciphering their role in inhibiting metastatic breast cancer.

Angiogenesis driven tumor initiation and progression calls for a targeted therapy. Moreover, combined chemotherapy supplements the therapy to act on the cause of concern. In this study, we aimed to develop a targeted crystalsomes approach to delineate tumor cells against normal cells. Self-assembled crystalline monodispersed nanosized polyethylene-polyethylene glycol (PE-PEG)-based hollow crystalsomes were modified with pluronylated putrescine (Put-PF) and loaded with doxorubicin (Dox), synergistically in combination with oleanolic acid (OA) to target the glypican-1 (gp-1) receptor on tumor cells. The developed crystalsomes (Put-D + O@NCs) showed increased intracellular accumulation of Dox and OA in a synergistic combination inside the MDA-MB-231 cell lines. The developed crystalsomes marked an enhanced depolarization of the mitochondrial membrane potential and cell cycle arrest leading to apoptosis. Furthermore, the proposed therapy has a greater anti-angiogenesis activity with vascular endothelial growth factor (VEGF) dependent modulation in the proliferation, invasion, migration and tube formation of human endothelial umbilical vein cells (HUVECs) in vitro and in vivo in a BALB/c mouse model. Interestingly, the perseverance of the tumor boundary, inhibiting the expression and activity of the matrix metalloproteinase (MMPs) (>5.2-fold) with suppressed degradation of the extracellular matrix paves the way for significant inhibition of metastases. However, an intravenously administered Put-D + O@NCs showed an improved pharmacokinetic profile and exquisite inhibition of the 4T1 induced tumor with a significantly lower toxicity. In a nutshell, these findings highlight the important role of Put in the gp-1 receptor for specific targeting and synergistic delivery of Dox and OA through crystalsomes as a potential approach for the treatment of metastatic breast cancer using combined chemotherapy.

Theranostic lyotropic liquid crystalline nanostructures for selective breast cancer imaging and therapy.

Herein, we report the development of theranostic lyotropic liquid crystalline nanostructures (LCN's) loaded with unique MnO nanoparticles (MNPs) for selective cancer imaging and therapy. MNPs serves as a fluorescent agent as well as a source of manganese (Mn2+) and enables localized oxidative stress under the hallmarks of cancer (acidosis, high H2O2 level). In pursuit of synergistic amplification of Mn2+ antitumor activity, betulinic acid (BA) is loaded in LCN's. In this investigation, nano-architecture of LCN's phase interface is established via SAXS, Cryo-TEM and Cryo-FESEM. Intriguing in vitro studies showed that the LCN's triggered hydroxyl radical production and exhibited greater selective cytotoxicity in cancer cells, ensuring the safety of normal cells. Significant tumor ablation is realized by the 96.5 % of tumor growth inhibition index of LCN's as compared to control group. Key insights into on-site drug release, local anti-cancer response, and tumor location are gained through precise guidance of fluorescent MNPs. In addition, comprehensive assessment of the safety, pharmacokinetics and tumor distribution behavior of LCN's is performed in vivo or ex vivo. This work emphasizes the promise of modulating tumor microenvironment with smart endogenous stimuli sensitive nano systems to achieve advanced comprehensive cancer nano-theranostics without any external stimulus. STATEMENT OF SIGNIFICANCE: Effective diagnosis and treatment approaches with maximum anti-cancer activity and minimal side-effects are critical to ameliorate cancer therapy. Compared to radiation, photodynamic and photothermal therapy, the specific and selective activation of tumor microenvironmental endogenous stimuli for the logical generation of cytotoxic OH· free radicals serves as an efficient therapeutic strategy for chemodynamic-cancer treatment. In this investigation, MnO nanoparticles fulfill two needs (fluorescence-based optical imaging and a source of Mn2+ based chemodynamic therapy) in one unit. This approach also ensures the safety of normal cells, as the toxic OH· free radical activity is substantially suppressed under the mild alkaline/H2O2 conditions in normal cell microenvironment.

Targeted co-delivery of the aldose reductase inhibitor epalrestat and chemotherapeutic doxorubicin via a redox-sensitive prodrug approach promotes synergistic tumor suppression.

Rapidly growing evidence suggests a strong dependence of a polyol pathway enzyme Aldose Reductase (AR) in cancer progression and invasion. Thus, inhibiting the AR through therapeutic inhibitors has a potential application in cancer treatment. Epalrestat (EPR) is the only marketed AR inhibitor with proven safety and efficacy in the management of complications like diabetic neuropathy. However, its short half-life and highly hydrophobic nature restrict its use as an anticancer agent. In the present study, we first developed a redox-sensitive prodrug of EPR by conjugating Tocopherol Polyethylene Glycol Succinate (TPGS) which can form a self-assembled micellar prodrug (EPR-SS-TPPGS). Subsequently, to achieve synergistic chemotherapeutic efficacy Doxorubicin (Dox) was co-loaded into the EPR-SS-TPGS micelles where the system is disrupted in a tumor redox environment and co-delivers Dox and EPR in a ratiometric manner. We then employed TPGS conjugated vitamin-B6 as a targeting moiety and prepared the mixed micelles to facilitate VTC receptor-mediated uptake. The encapsulation of Dox and EPR with the developed prodrug approach showed significant synergies with increased intracellular accumulation and redox triggered release in MDA-MB-231 and 4T1 cell lines leading to superior cell cycle arrest, mitochondrial membrane potential, and apoptosis. Prolonged circulation half-life and tumor site bioavailability were achieved for both the drugs with the developed approach. Surprisingly, EPR and Dox combination significantly down-regulated the CD44 receptor expression which is the main contributing factor of tumor metastasis. Furthermore, in vivo evaluation demonstrated a significant reduction in Dox-induced cardiotoxicity. In summary, this nanoencapsulation paradigm of AR inhibitors with chemotherapeutic agents lays the foundation of new opportunities in combination chemotherapy.

Nonlamellar liquid crystals: a new paradigm for the delivery of small molecules and bio-macromolecules.

The aim of this article is to collate the recent developments in the field of drug delivery, medical therapeutics and diagnostics specifically involving the nonlamellar liquid crystalline (NLC) systems. This review highlights different NLC phases having cubic, hexagonal and sponge internal structures, and their application in the field of drug delivery, such as dose reduction, toxicity reduction and therapeutic efficacy enhancement either in the form of nanoparticles, colloidal dispersion or gels. In addition, application of NLC systems as vehicles for peptides, proteins and as a theranostic system in cancer and other disease conditions is also elaborated, which is a growing platform of interest. Overall, the present review gives us a complete outlook on applications of NLC systems in the field of medicine.