Recent advances in nano-based drug delivery systems for treatment of liver cancer.

Liver cancer is one of the aggressive primary tumors as evident by high rate of incidence and mortality. Conventional treatments (e.g. chemotherapy) suffer from various drawbacks including wide drug distribution, low localized drug concentration, and severe off-site toxicity. Therefore, they cannot satisfy the mounting need for safe and efficient cancer therapeutics, and alternative novel strategies are needed. Nano-based drug delivery systems (NDDSs) are among these novel approaches that can improve the overall therapeutic outcomes. NDDSs are designed to encapsulate drug molecules and target them specifically to liver cancer. Thus, NDDSs can selectively deliver therapeutic agents to the tumor cells and avoid distribution to off-target sites which should improve the safety profile of the active agents. Nonetheless, NDDSs should be well designed, in terms of the preparing materials, nanocarriers structure, and the targeting strategy, in order to accomplish these objectives. This review discusses the latest advances of NDDSs for cancer therapy with emphasis on the aforementioned essential design components. The review also entails the challenges associated with the clinical translation of NDDSs, and the future perspectives towards next-generation NDDSs.

Engineering nanomedicines for immunogenic eradication of cancer cells: Recent trends and synergistic approaches.

Resistance to cancer immunotherapy is mainly attributed to poor tumor immunogenicity as well as the immunosuppressive tumor microenvironment (TME) leading to failure of immune response. Numerous therapeutic strategies including chemotherapy, radiotherapy, photodynamic, photothermal, magnetic, chemodynamic, sonodynamic and oncolytic therapy, have been developed to induce immunogenic cell death (ICD) of cancer cells and thereby elicit immunogenicity and boost the antitumor immune response. However, many challenges hamper the clinical application of ICD inducers resulting in modest immunogenic response. Here, we outline the current state of using nanomedicines for boosting ICD of cancer cells. Moreover, synergistic approaches used in combination with ICD inducing nanomedicines for remodeling the TME via targeting immune checkpoints, phagocytosis, macrophage polarization, tumor hypoxia, autophagy and stromal modulation to enhance immunogenicity of dying cancer cells were analyzed. We further highlight the emerging trends of using nanomaterials for triggering amplified ICD-mediated antitumor immune responses. Endoplasmic reticulum localized ICD, focused ultrasound hyperthermia, cell membrane camouflaged nanomedicines, amplified reactive oxygen species (ROS) generation, metallo-immunotherapy, ion modulators and engineered bacteria are among the most innovative approaches. Various challenges, merits and demerits of ICD inducer nanomedicines were also discussed with shedding light on the future role of this technology in improving the outcomes of cancer immunotherapy.

Modulating tumoral exosomes and fibroblast phenotype using nanoliposomes augments cancer immunotherapy.

Cancer cells program fibroblasts into cancer associated fibroblasts (CAFs) in a two-step manner. First, cancer cells secrete exosomes to program quiescent fibroblasts into activated CAFs. Second, cancer cells maintain the CAF phenotype via activation of signal transduction pathways. We rationalized that inhibiting this two-step process can normalize CAFs into quiescent fibroblasts and augment the efficacy of immunotherapy. We show that cancer cell-targeted nanoliposomes that inhibit sequential steps of exosome biogenesis and release from lung cancer cells block the differentiation of lung fibroblasts into CAFs. In parallel, we demonstrate that CAF-targeted nanoliposomes that block two distinct nodes in fibroblast growth factor receptor (FGFR)-Wnt/ß-catenin signaling pathway can reverse activate CAFs into quiescent fibroblasts. Co-administration of both nanoliposomes significantly improves the infiltration of cytotoxic T cells and enhances the antitumor efficacy of αPD-L1 in immunocompetent lung cancer-bearing mice. Simultaneously blocking the tumoral exosome-mediated activation of fibroblasts and FGFR-Wnt/ß-catenin signaling constitutes a promising approach to augment immunotherapy.

Nanomedicines as enhancers of tumor immunogenicity to augment cancer immunotherapy.

The potential of cancer immunotherapy is hampered by the poor immunogenicity of cancer cells. Strategies to enhance tumor immunogenicity are imperative to enhance T cell-mediated anti-tumor immunity. Although conventional therapeutics can increase tumor antigen expression or stimulate the release of danger signals to promote immunogenic cell death (ICD), they face challenges relating to efficacy and tumor-specific delivery. Nanomedicines can efficiently deliver tumor antigens, immune adjuvants, epigenetic modulators, or ICD inducers through targeted drug delivery with minimal off-target effects. Collectively, nanomedicines can overcome biological barriers to immunotherapy through targeted antigen delivery, induction of ICD, or epigenetic remodeling, resulting in increased tumor immunogenicity.

Engineered Microencapsulated Lactoferrin Nanoconjugates for Oral Targeted Treatment of Colon Cancer.

Despite current progress in the development of targeted therapies for cancer treatment, there is a lack in convenient therapeutics for colorectal cancer (CRC). Lactoferrin nanoparticles (Lf NPs) are a promising drug delivery system in cancer therapy. However, numerous obstacles impede their oral delivery, including instability against stomach enzymes and premature uptake during passage through the small intestine. Microencapsulation of Lf NPs offer a great solution for these obstacles. It can protect Lf NPs and their drug payloads from degradation in the upper gastrointestinal tract (GIT), reduce burst drug release, and improve the release profile of the encapsulated NPs triggered by stimuli in the colon. Here, we developed nanoparticle-in-microparticle delivery systems (NIMDs) for the oral delivery of docetaxel (DTX) and atorvastatin (ATR). The NPs were obtained by dual conjugation of DTX and ATR into the Lf backbone, which was further microencapsulated into calcium-crosslinked microparticles using polysaccharide-protein hybrid copolymers. The NIMDs showed no detectable drug release in the upper GIT compared to NPs. Furthermore, sustained release of the NPs from the NIMDs in rat cecal content was observed. Moreover, the in vivo study demonstrated the superiority of the NIMDs over NPs in CRC treatment by suppressing p-AKT, p-ERK1/2, and NF-κB. This study provides the proof of concept for using NIMDs to enhance the effect of protein NPs in CRC treatment.

Engineered Sericin-Tagged Layered Double Hydroxides for Combined Delivery of Pemetrexed and ZnO Quantum Dots as Biocompatible Cancer Nanotheranostics.

AIM: Despite extensive progress in the field of cancer nanotheranostics, clinical development of biocompatible theranostic nanomedicine remains a formidable challenge. Herein, we engineered biocompatible silk-sericin-tagged inorganic nanohybrids for efficient treatment and imaging of cancer cells. The developed nanocarriers are anticipated to overcome the premature release of the chemotherapeutic drug pemetrexed (PMX), enhance the colloidal stability of layered double hydroxides (LDHs), and maintain the luminescence properties of ZnO quantum dots (QDs). Materials and Methods: PMX-intercalated LDHs were modified with sericin and coupled to ZnO QDs for therapy and imaging of breast cancer cells. Results: The optimized nanomedicine demonstrated a sustained release profile of PMX, and high cytotoxicity against MDA-MB-231 cells compared to free PMX. In addition, high cellular uptake of the engineered nanocarriers into MDA-MB-231 breast cancer cells was accomplished. Conclusions: Conclusively, the LDH-sericin nanohybrids loaded with PMX and conjugated to ZnO QDs offered a promising cancer theranostic nanomedicine.

Combined Cancer Immunotheranostic Nanomedicines: Delivery Technologies and Therapeutic Outcomes.

Cancer is among the main causes of mortality all over the world. The delayed diagnosis is directly related to the decrease in survival rate. The use of immunotherapy has dramatically changed the treatment outcomes of different types of cancers. However, many patients still do not respond to immunotherapies, and many also suffer from severe immune-related side effects. Recent advances in the fields of nanomedicine bioengineering and in particular imaging offered new approaches which can enhance not only the safety but also the efficacy of immunotherapy. Theranostics has showed great progress as a branch of medicine which integrates both diagnosis and therapy in a single system. The outcomes from animal studies demonstrated an improvement in the diagnostic and immunotherapeutic potential of nanoparticles within the theranostic framework. Herein, we discuss the most recent developments in the application of nanotheranostics for combining tumor imaging and cancer immunotherapies.

Engineered nanomedicines to overcome resistance of pancreatic cancer to immunotherapy.

Pancreatic cancer (PC) is a highly aggressive malignant type of cancer. Although immunotherapy has been successfully used for treatment of many cancer types, many challenges limit its success in PC. Therefore, nanomedicines were engineered to enhance the responsiveness of PC cells to immune checkpoint inhibitors (ICIs). In this review, we highlight recent advances in engineering nanomedicines to overcome PC immune resistance. Nanomedicines were used to increase the immunogenicity of PC cells, inactivate stromal cancer-associated fibroblasts (CAFs), enhance the antigen-presenting capacity of dendritic cells (DCs), reverse the highly immunosuppressive nature of the tumor microenvironment (TME), and, hence, improve the infiltration of cytotoxic T lymphocytes (CTLs), resulting in efficient antitumor immune responses.

Sequential Delivery of Novel Triple Drug Combination via Crosslinked Alginate/Lactoferrin Nanohybrids for Enhanced Breast Cancer Treatment.

While breast cancer remains a global health concern, the elaboration of rationally designed drug combinations coupled with advanced biocompatible delivery systems offers new promising treatment venues. Herein, we repurposed rosuvastatin (RST) based on its selective tumor apoptotic effect and combined it with the antimetabolite pemetrexed (PMT) and the tumor-sensitizing polyphenol honokiol (HK). This synergistic three-drug combination was incorporated into protein polysaccharide nanohybrids fabricated by utilizing sodium alginate (ALG) and lactoferrin (LF), inspired by the stealth property of the former and the cancer cell targeting capability of the latter. ALG was conjugated to PMT and then coupled with LF which was conjugated to RST, forming core shell nanohybrids into which HK was physically loaded, followed by cross linking using genipin. The crosslinked HK-loaded PMT-ALG/LF-RST nanohybrids exhibited a fair drug loading of 7.86, 5.24 and 6.11% for RST, PMT and HK, respectively. It demonstrated an eight-fold decrease in the IC50 compared to the free drug combination, in addition to showing an enhanced cellular uptake by MCF-7 cells. The in vivo antitumor efficacy in a breast cancer-bearing mouse model confirmed the superiority of the triple cocktail-loaded nanohybrids. Conclusively, our rationally designed triple drug-loaded protein/polysaccharide nanohybrids offer a promising, biocompatible approach for an effective breast tumor suppression.

Green self-assembled lactoferrin carboxymethyl cellulose nanogels for synergistic chemo/herbal breast cancer therapy.

The current treatment protocols for breast cancer have shifted from single agent therapies to combinatorial approaches that offer synergistic efficacies and reduced side effects. Self-assembled nanogels comprising natural polysaccharides and functional proteins provide an intelligent platform for the targeted co-delivery of therapeutic molecules. Herein, we report the fabrication of self-assembled nanogels utilizing hydrophilic biocompatible proteins, lactoferrin (Lf), and polysaccharide carboxy methyl cellulose (CMC), for the combined delivery of the antimetabolite pemetrexed (PMT) and the herbal polyphenol honokiol (HK). PMT was conjugated to LF via an amide bond. The conjugate was then electrostatically assembled into CMC under optimized conditions to form nanogels (Lf-CMC NGs). An inclusion complex of HK with hydroxypropyl-ß-cyclodextrin was then encapsulated in the prepared Lf-CMC NGs with an entrapment efficiency of 66.67%. The dual drug-loaded cross-linked Lf-CMC NGs exhibited a particle size of 193.4 nm and zeta potential of - 34.5 mV and showed a sustained release profile for both drugs. PMT/HK-loaded Lf-CMC NGs were successfully taken up by MDA-MB-231 breast cancer cells and demonstrated superior in vitro cytotoxicity, as elucidated by a low combination index value (CI=0.17) and a higher dose reduction index (DRI) compared to those of the free drugs. An in vivo antitumor study using an Ehrlich ascites tumor (EAT) mouse model revealed the robust efficacy of PMT/HK-loaded Lf-CMC NGs in inhibiting tumor growth, which was ascribed to the reduced expression level of VEGF-1, elevated protein expression level of caspase-3, and suppressed Ki-67 protein level in the tumor tissue (P ˂0.05). In conclusion, our green fabricated self-assembled dual-loaded nanogels offer a promising biocompatible strategy for targeted combinatorial breast cancer therapy.

Methotrexate-Lactoferrin Targeted Exemestane Cubosomes for Synergistic Breast Cancer Therapy.

While the treatment regimen of certain types of breast cancer involves a combination of hormonal therapy and chemotherapy, the outcomes are limited due to the difference in the pharmacokinetics of both treatment agents that hinders their simultaneous and selective delivery to the cancer cells. Herein, we report a hybrid carrier system for the simultaneous targeted delivery of aromatase inhibitor exemestane (EXE) and methotrexate (MTX). EXE was physically loaded within liquid crystalline nanoparticles (LCNPs), while MTX was chemically conjugated to lactoferrin (Lf) by carbodiimide reaction. The anionic EXE-loaded LCNPs were then coated by the cationic MTX-Lf conjugate via electrostatic interactions. The Lf-targeted dual drug-loaded LCNPs exhibited a particle size of 143.6 ± 3.24 nm with a polydispersity index of 0.180. It showed excellent drug loading with an EXE encapsulation efficiency of 95% and an MTX conjugation efficiency of 33.33%. EXE and MTX showed synergistic effect against the MCF-7 breast cancer cell line with a combination index (CI) of 0.342. Furthermore, the Lf-targeted dual drug-loaded LCNPs demonstrated superior synergistic cytotoxic activity with a combination index (CI) of 0.242 and a dose reduction index (DRI) of 34.14 and 4.7 for EXE and MTX, respectively. Cellular uptake studies demonstrated higher cellular uptake of Lf-targeted LCNPs into MCF-7 cancer cells than non-targeted LCNPs after 4 and 24 h. Collectively, the targeted dual drug-loaded LCNPs are a promising candidate offering combinational hormonal therapy/chemotherapy for breast cancer.

Engineered nanomedicines for augmenting the efficacy of colorectal cancer immunotherapy.

Colorectal cancer (CRC) is one of the most devastating diseases worldwide. Immunotherapeutic agents for CRC treatment have shown limited efficacy due to the immunosuppressive tumor microenvironment (TME). In this context, various types of nanoparticles (NPs) have been used to reverse the immunosuppressive TME, potentiate the effect of immunotherapeutic agents and reduce their systemic side effects. Many advantages could be offered by NPs, related to drug-loading efficiency, particle size and others that can potentially aid the delivery of immunotherapeutic agents. The recent research on how nano-based immunotherapy can remodel the immunosuppressive TME of CRC and hence boost the antitumor immune response, as well as the challenges that face clinical translation of NPs and future perspectives, are summarized in this review article.

Recent advances in nanomedicine-based delivery of histone deacetylase inhibitors for cancer therapy.

Histone deacetylase inhibitors (HDACi) are cancer therapeutics that operate at the epigenetic level and which have recently gained wide attention. However, the applications of HDACi are generally hindered by their poor physicochemical characteristics and unfavorable pharmacokinetic profile. Inspired by the approved nanomedicine-based drugs in the market, nanocarriers could provide a resort to circumvent the limitations imposed by HDACi. Enhanced tumor targeting, improved cellular uptake and reduced toxicity are major advantages offered by HDACi-loaded nanoparticles. More importantly, site-specific drug delivery can be achieved via engineered stimuli-responsive nanosystems. In this review we elucidate the anticancer mechanisms of HDACi and their structure-activity relationships, with a special focus on their nanomedicine-based delivery, different drug loading concepts and their implications.

Recent advances in herbal combination nanomedicine for cancer: delivery technology and therapeutic outcomes.

Introduction: The use of herbal compounds in cancer therapy has great potential to promote the efficacy of current cancer therapeutic strategies. Herbal compounds were successfully reported to enhance tumor cells sensitization to the action of chemo-, hormonal- and gene-therapeutic agents via different mechanisms. Herbal ingredients can affect different signaling pathways, reduce the toxic side effects or inhibit the efflux of anticancer drugs.Areas covered: This review will discuss the delivery of herbal compounds with other cancer treatments such as hormonal, small molecule inhibitors and inorganic hybrids to tumor cells. An overview of physicochemical properties of herbal components that require intelligent design of combo-nanomedicines for efficient co-delivery of those herbal-derived and other anticancer agents was discussed. Nanocarriers provide various benefits to overcome the shortcomings of the encapsulated herbal compounds including improved solubility, increased stability and enhanced tumor targeting. Different nanocarrier systems were the focus of this review.Expert opinion: Multifunctional nanocarrier systems encapsulating herbal and different anticancer drugs showed to be a wonderful approach in the treatment of cancer enabling the co-delivery of anticancer drugs with versatile modes of action in an accurate manner in an attempt to enhance the efficacy, benefit from the synergism between the drugs as well as to minimize the development of multi-drug resistance. The main challenge point is the early detection and management of any developed adverse effect.

Celecoxib repurposing in cancer therapy: molecular mechanisms and nanomedicine-based delivery technologies.

While cancer remains a significant global health problem, advances in cancer biology, deep understanding of its underlaying mechanism and identification of specific molecular targets allowed the development of new therapeutic options. Drug repurposing poses several advantages as reduced cost and better safety compared with new compounds development. COX-2 inhibitors are one of the most promising drug classes for repurposing in cancer therapy. In this review, we provide an overview of the detailed mechanism and rationale of COX-2 inhibitors as anticancer agents and we highlight the most promising research efforts on nanotechnological approaches to enhance COX-2 inhibitors delivery with special focus on celecoxib as the most widely studied agent for chemoprevention or combined with chemotherapeutic and herbal drugs for combating various cancers.

Recent advances in polymer shell oily-core nanocapsules for drug-delivery applications.

Polymeric nanocapsules are vesicular drug-delivery systems composed of an inner oily reservoir surrounded by polymeric membranes. Nanocapsules have various advantages over other nanovesicular systems such as providing controlled drug release properties. We discuss the recent advances in polymeric shell oily-core nanocapsules, illustrating the different types of polymers used and their implementation. Nanocapsules can be utilized for many purposes, especially encapsulation of highly lipophilic drugs. They have been shown to have variable applications, especially in cancer therapy, due to the ability of the polymeric shell to direct the loaded drugs to their target sites, as well as their high internalization efficacy. Those productive applications guaranteed their high potential as drug-delivery systems. However, their clinical development is still in an early stage.

A novel 'smart' PNIPAM-based copolymer for breast cancer targeted therapy: Synthesis, and characterization of dual pH/temperature-responsive lactoferrin-targeted PNIPAM-co-AA.

Despite the active research towards introducing novel anticancer agents, the long-term sequelae and side effects of chemotherapy remain the major obstacle to achieving clinical success. Recent cancer research is now utilizing the medicinal chemistry toolbox to tailor novel 'smart' carrier systems that can reduce the major limitations of chemotherapy ranging from non-specificity and ubiquitous biodistribution to systemic toxicity. In this aspect, various stimuli-responsive polymers have gained considerable interest due to their intrinsic tumor targeting properties. Among these polymers, poly(N-isopropylacrylamide (PNIPAM) has been chemically modified to tune its thermoresponsivity or even copolymerized to endow new stimulus responsiveness for enhancing tumor targeting. Herein, we set our design rationale to impart additional active targeting entity to pH/temperature-responsive PNIPAM-based polymer for more efficient controlled payloads accumulation at the tumor through cellular internalization via synthesizing novel "super intelligent" lactoferrin conjugated PNIPAM-acrylic acid (LF-PNIPAM-co-AA) copolymer. The synthesized copolymer was physicochemically characterized and evaluated as a smart nanocarrier for targeting breast cancer. In this regard, Honokiol (HK) was utilized as a model anticancer drug and encapsulated in the nanoparticles to overcome its lipophilic nature and allow its parenteral administration, for achieving sustainable drug release with targeting action. Results showed that the developed HK-loaded LF-PNIPAM-co-AA nanohydrogels displayed high drug loading capacity reaching to 18.65 wt.% with excellent physical and serum stability. Moreover, the prepared HK-loaded nanohydrogels exhibited efficient in vitro and in vivo antitumor activities. In vivo, HK-loaded nanohydrogels demonstrated suppression of VEGF-1 and Ki-67 expression levels, besides inducing apoptosis through upregulating the expression level of active caspase-3 in breast cancer-bearing mice. Overall, the developed nanohydrogels (NGs) with pH and temperature responsivity provide a promising nanocarrier for anticancer treatment.

Lactoferrin-dual drug nanoconjugate: Synergistic anti-tumor efficacy of docetaxel and the NF-κB inhibitor celastrol.

Despite the progress in cancer nanotherapeutics, some obstacles still impede the success of nanocarriers and hinder their clinical translation. Low drug loading, premature drug release, off-target toxicity and multi-drug resistance are among the most difficult challenges. Lactoferrin (LF) has demonstrated a great tumor targeting capacity via its high binding affinity to low density lipoprotein (LDL) and transferrin (Tf) receptors overexpressed by various cancer cells. Herein, docetaxel (DTX) and celastrol (CST) could be successfully conjugated to LF backbone for synergistic breast cancer therapy. Most importantly, the conjugate self-assembled forming nanoparticles of 157.8 nm with elevated loading for both drugs (6.94 and 5.98% for DTX and CST, respectively) without risk of nanocarrier instability. Moreover, the nanoconjugate demonstrated enhanced in vivo anti-tumor efficacy in breast cancer-bearing mice, as reflected by a reduction in tumor volume, prolonged survival rate and significant suppression of NF-κB p65, TNF-α, COX-2 and Ki-67 expression levels compared to the group given free combined DTX/CST therapy and to positive control. This study demonstrated the proof-of-principle for dual drug coupling to LF as a versatile nanoplatform that could augment their synergistic anticancer efficacy.

Dual Therapeutic Targeting of Lung Infection and Carcinoma Using Lactoferrin-Based Green Nanomedicine.

In view of the promising applications of nanoparticles in drug delivery, this study highlights the fabrication of new bioactive green protein-polysaccharide nanocomplexes with significant antibacterial and antitumor efficacies. We preformulated the water-insoluble drugs Quercetin (Quer) and Resveratrol (Res) as water-soluble nanocrystals to facilitate their entrapment in the electrostatic lactoferrin-chondroitin (Lf-ChS) nanocomplex. Quer and Res were physically entrapped in the Lf-ChS nanomatrix with high encapsulation efficiencies (EE %) of 85.2 and 90.1% w/w for Quer and Res, respectively. The in vitro synergetic antibacterial effects of the studied compounds against all bacterial strains were confirmed. Res-Quer Lf-ChS NPs revealed an enhanced cytotoxic effect against A549 lung cancer cells. A new model of polymicrobial lung infection was designed, where treatment with Res-Quer Lf-ChS NPs (233.5 ± 6.59 nm) resulted in a marked decline of 3.2 log units in bacterial counts. In the lung tumor model, the potent antitumor efficacy of the developed Res-Quer Lf-ChS NPs was demonstrated by a noticeable decline in both lung weight and the biomarkers compared to the positive control group that did not receive any treatment. In conclusion, the green Res-Quer Lf-ChS NPs possess antibacterial and antitumor attributes for potential lung infection and tumor therapy.

Lactoferrin, a multi-functional glycoprotein: Active therapeutic, drug nanocarrier & targeting ligand.

Recent progress in protein-based nanomedicine, inspired by the success of Abraxane® albumin-paclitaxel nanoparticles, have resulted in novel therapeutics used for treatment of challenging diseases like cancer and viral infections. However, absence of specific drug targeting, poor pharmacokinetics, premature drug release, and off-target toxicity are still formidable challenges in the clinic. Therefore, alternative protein-based nanomedicines were developed to overcome those challenges. In this regard, lactoferrin (Lf), a glycoprotein of transferrin family, offers a promising biodegradable well tolerated material that could be exploited both as an active therapeutic and drug nanocarrier. This review highlights the major pharmacological actions of Lf including anti-cancer, antiviral, and immunomodulatory actions. Delivery technologies of Lf to improve its pries and enhance its efficacy were also reviewed. Moreover, different nano-engineering strategies used for fabrication of drug-loaded Lf nanocarriers were discussed. In addition, the use of Lf for functionalization of drug nanocarriers with emphasis on tumor-targeted drug delivery was illustrated. Besides its wide application in oncology nano-therapeutics, we discussed the recent advances of Lf-based nanocarriers as efficient platforms for delivery of anti-parkinsonian, anti-Alzheimer, anti-viral drugs, immunomodulatory and bone engineering applications.