Molecular targeting of drug delivery systems to cancer

This review presents molecular targeting approaches in anticancer drug delivery systems (DDS) and identifies new developments in these systems. Targeting approaches include passive targeting (enhanced permeability and retention effect), targeting specific tumor conditions, topical delivery and active targeting, namely, targeting organs, cells, intracellular organelles and molecules, sandwich targeting, promoter targeting, indirect targeting and targeting by external stimuli. A novel advanced proapoptotic anticancer DDS that utilizes several molecular targets will be considered. Experimental data suggest that this DDS can simultaneously: (1) induce cell death, (2) prevent adverse effects on healthy tissues; (3) suppress and prevent multidrug resistance; and (4) inhibit cellular antiapoptotic defense.     

Targeted proapoptotic anticancer drug delivery system

A novel targeted proapoptotic anticancer drug delivery system (DDS) was developed and evaluated both in vitro and in vivo. The system contains poly(ethylene glycol) polymer (PEG) as a carrier, camptothecin (CPT) as an anticancer drug/cell death inducer, a synthetic analogue of luteinizing hormone-releasing hormone (LHRH) peptide as a targeting moiety/penetration enhancer, and a synthetic analogue of BCL2 homology 3 domain (BH3) peptide as a suppressor of cellular antiapoptotic defense. The design of the multicomponent DDS allowed for a conjugation of one or two copies of each active ingredient (CPT, LHRH, and BH3) to one molecule of PEG carrier. The complex structure of the PEG conjugates was visualized at nanometer resolution using atomic force microscopy. We found that the ligand-targeted DDS for cancer cells preferentially accumulated in the tumor and allowed the delivery of active ingredients into the cellular cytoplasm and nuclei of cancer cells. Simultaneous apoptosis induction through the caspase-dependent signaling pathway and inhibition of cellular antiapoptotic defense by the suppression of BCL2 protein enhanced cytotoxicity and antitumor activity of the entire DDS to a level which could not be achieved by individual components applied separately. The DDS containing two copies of each active component (CPT, LHRH, and BH3) per molecule of PEG polymer had the highest anticancer efficiency in vitro and in vivo.     

Pharmacokinetics and pharmacodynamics of lipidic nano-particles in cancer

Nanoscale drug delivery systems (DDS) are used to circumvent some of the non-ideal properties of conventional anticancer chemotherapy drugs. Manipulation of the physical properties of DDS provides improved control over the pharmacokinetics (PK) and pharmacodynamics (PD) of the encapsulated drugs relative to free drugs. Liposomes are the archetypical nanoscale DDS and the first of these received clinical approval in 1990. DOXIL, liposomal doxorubicin, was the first commercially available liposomal anticancer drug (1995). It has an enhanced circulation half-life compared to the free drug because of its surface-grafted polyethylene glycol coating. DOXIL passively targets solid tumors, and once the liposomes localize in the tumor interstitial space, the cytotoxic drug is slowly released within the tumor. Liposomes can act as sustained release delivery system and manipulation of properties such as, liposome diameter, drug release rate, bioavailability and dosing schedule can significantly impact the therapeutic outcome of the liposomal drugs. This review will focus on how alteration of these properties can impact the therapeutic efficacy and side effect profiles of DDS.     

Triggered activation and release of liposomal prodrugs and drugs in cancer tissue by secretory phospholipase A2

The selectivity of anticancer drugs in targeting the tumour tissue presents a major problem in cancer treatment. In this article we review a new generation of smart liposomal nanocarriers that can be used for enhanced anticancer drug and prodrug delivery to tumours. The liposomes are engineered to be particularly degradable to secretory phospholipase A2 (sPLA2), which is a lipid hydrolyzing enzyme that is significantly upregulated in the extracellular microenvironment of cancer tumours. Thus, when the long circulatory liposomal nanocarriers extravasate and accumulate in the interstitial tumour space, sPLA2 will act as an active trigger resulting in the release of cytotoxic drugs in close vicinity of the target cancer cells. The sPLA2 generated lysolipid and fatty acid hydrolysis products will furthermore be locally released and function as membrane permeability promoters facilitating the intracellular drug uptake. In addition, the liposomal membrane can be composed of a novel class of prodrug lipids that can be converted selectively to active anticancer agents by sPLA2 in the tumour. The integrated drug discovery and delivery technology offers a promising way to rationally design novel tumour activated liposomal nanocarriers for better cancer treatment.     

Drug targeting to the colon with lectins and neoglycoconjugates

Targeting of drugs to specific sites of action provides several advantages over non-targeted drugs. These include the prevention of side effects of drugs on healthy tissues and enhancement of drug uptake by targeted cells. This review will cover traditional approaches of colon drug targeting as well as the use of lectins and neoglycoconjugates for the targeted delivery. Direct and reverse targeting strategies, potential molecular targets and targeting moieties for colon drug delivery, targeted drug delivery systems (DDS) for colon delivery, anticancer DDS targeted to colon cancer are examined. Directions of future development are discussed.     

Pharmacokinetics of targeting with liposomes

The optimization of drug disposition in the body leads to an increase in its therapeutic effect and to a decrease in adverse effects. Liposomes can serve as a potential drug carrier for achieving this. However, the behavior of a drug carrier system under in vivo conditions is complex. Therefore, a more complete understanding of the pharmacokinetics of liposomes themselves, as well as that of the encapsulated drug, is required. The optimization of the pharmacokinetics of liposomes can be performed by linking a pharmacodynamic model of the free drugs that are encapsulated into liposomes. Sensitivity analysis was applied to optimize the delivery system to maximize the antitumor effect of liposomal doxorubicin (DOX). Advanced technology for ligand-mediated selective targeting and intracellular targeting is also introduced for antitumor agents and for gene delivery systems.     

Simultaneous Modulation of Multidrug Resistance and Antiapoptotic Cellular Defense by MDR1 and BCL-2 Targeted Antisense Oligonucleotides Enhances the Anticancer Efficacy of Doxorubicin

Purpose. To enhance the anticancer efficacy of an established drug by the simultaneous suppression of pump and nonpump cellular resistance. Methods. Multidrug resistant human ovarian (A2780/AD) and breast (MCF-7/AD) cancer cells were used. Doxorubicin (DOX) and antisense oligonucleotides (ASO) targeted to MDR1 and BCL-2 mRNA were combined in a solution within one liposomal drug delivery system (LDDS) in different combination series. Ten series of experiments were performed. In each series cells were incubated with 12 to 45 concentrations of free DOX and different liposomal formulations over a period of 6 to 48 h. Cytotoxicity, apoptosis induction, caspases, MDR1, BCL-2, and APAF-1 genes, P-glycoprotein, and BCL-2 protein were studied. Results. The combination of DOX and ASO targeted to MDR1 and BCL-2 mRNA in one LDDS exhibited a dramatic increase in the anticancer action of DOX. As a result of the simultaneous suppression of pump and nonpump cellular resistance by the inhibition of P-glycoprotein and BCL-2 protein synthesis, a significant increase in the activation of caspases and apoptosis was observed. Conclusions. The simultaneous suppression of multidrug resistance and antiapoptotic cellular defense significantly enhanced the anticancer activity of DOX. Therefore, the proposed DDS combination may potentially be used in the treatment of multidrug-resistant ovarian and breast cancers.     

Expedition of liposomes to intracellular targets in solid tumors after intravenous administration

Liposomes as a drug delivery system provides a leading approach for the systemic (intravenous) administration of drugs. Several approaches to kill tumor cells specifically have been developed, but still there is dearth in their selectivity. Among all other nano-carrier systems, liposomal formulations of cytotoxic drugs have received an appreciable recommendation in the form of clinical approvals. Liposomal delivery provides the benefits of reduced toxicity and enhanced efficacy for the treatment of cancer. However, delivery of liposomes to desired cell type with its further trafficking to desired intracellular organelle is a challenging, yet a promising approach for safer cancer therapeutics. Several anatomical-physiological barriers starting from systemic to cellular to intracellular levels are required to be overcome to achieve efficient cancer therapy. This review discusses the barriers associated with the delivery of liposomes from the extracellular to intracellular compartments of a solid tumor and further summarizes the development of liposomal carrier system to overcome these barriers.     

Molecular targeting of liposomal nano-particles to lymphatic system

Conventional liposomal drug delivery has been associated with obvious limitations, such as a rapid absorption by the recticulo-endothelial system in the liver and spleen, a short circulation time and a low therapeutic efficacy. Various modifications of liposomal drugs have been developed to prolong the duration of actions of the drugs at target sites, reduce its adverse effects and increase therapeutic index of drugs such as polymeric conjugation and polymeric fixation on the surface of a liposome. The lymphatic system is an important highway to spread the metastasis of most human cancers including breast, colon, and lung, ovarian and prostate. To eradicate those metastatic cancer cells from the lymphatic system, several efforts have been made to develop new and efficient lymphatic targeting drug delivery systems in order to achieve a high initial lymphatic uptake and lymph node localization. Recently, molecule targeting of liposome to lymphatic system may enhance therapeutic efficacy by improving the initial lymphatic uptake and the lymph nodal retention of liposomes such as the ligand-receptor and antibodies binding on the surface of liposome. This article aims to review the emerging liposomal drug, which is targeting the lymphatic system. The significant factors associated with targeting liposomal drugs will also be discussed in more detail in this review.     

Challenges in Development of Targeted Liposomal Therapeutics

Liposomes, phospholipid vesicles with a bilayered membrane structure, have been widely used as pharmaceutical carriers for drugs and genes, in particular for treatment of cancer. To enhance the efficacy of the liposomal drugs, drug-loaded liposomes are targeted to the tumors by means of passive (enhanced permeability and retention mediated) targeting, based on the longevity of liposomes in blood and its accumulation in pathological sites with compromised vasculature, and active targeting, based on the attachment of specific ligands to the liposomal surface to bind certain antigens on the target cells. Antibody-targeted liposomes loaded with anticancer drugs demonstrate high potential for clinical applications. This review highlights evolution of liposomes for both passive and active targeting and challenges in development of targeted liposomal therapeutics specifically antibody-targeted liposomes.     

主动靶向脂质体在抗肿瘤治疗中的研究进展

主动靶向脂质体给药系统可使抗肿瘤药物与靶组织结合,将药物可控性地分布于靶组织并持续缓慢释药,在提高药物抗癌效果的同时,降低了其对正常组织的不良反应。本文主要介绍了免疫脂质体、受体介导的脂质体、糖基修饰的脂质体及多肽修饰的脂质体等主动靶向脂质体在抗肿瘤研究中的进展。主动靶向脂质体给药系统将会发展为抗肿瘤药物的理想剂型,具有很好的临床应用前景。     

Neutrophil-mediated delivery of pixantrone-loaded liposomes decorated with poly(sialic acid)–octadecylamine conjugate for lung cancer treatment

Poly(sialic acid) (PSA) is a natural hydrophilic biodegradable and non-immunogenic biopolymer, receptors for its monomer are expressed on peripheral blood neutrophils (PBNs), which plays important roles in the progression and invasion of tumors. A poly(sialic acid)–octadecylamine conjugate (PSA–ODA) was synthesized and then anchor it on the surface of liposomal pixantrone (Pix-PSL), to achieve an improved anticancer effect. The liposomes were prepared using a remote loading method via a pH gradient, and then assessed for particle size, zeta potential encapsulation efficiency, in vitro release, and in vitro cytotoxicity. Simultaneously, in vitro and in vivo cellular uptake studies confirmed that PSA-decorated liposomes provided an enhanced accumulation of liposomes in PBNs. An in vivo study presented that the anti-tumor activity of Pix-PSL was superior to that of other Pix formulations, probably due to the efficient targeting of PBNs by Pix-PSL, after which PBN containing Pix-PSL (Pix-PSL/PBNs) in the blood circulation are recruited by the tumor microenvironment. These findings suggest that PSA-decorated liposomal Pix may provide a neutrophil-mediated drug delivery system (DDS) for the eradication of tumors, which represents a promising approach for the tumor targeting of chemotherapeutic treatments.     

Targeting Anticancer Drugs to Tumor Vasculature Using Cationic Liposomes

Liposomal drug delivery systems improve the therapeutic index of chemotherapeutic agents, and the use of cationic liposomes to deliver anticancer drugs to solid tumors has recently been recognized as a promising therapeutic strategy to improve the effectiveness of conventional chemotherapeutics. This review summarizes the selective targeting of cationic liposomes to tumor vasculature, the merits of incorporating the polymer polyethylene-glycol (PEG), and the impact of the molar percent of the cationic lipid included in cationic liposomes on liposomal targeting efficacy. In addition, the discussion herein includes the therapeutic benefit of a dual targeting approach, using PEG-coated cationic liposomes in vascular targeting (of tumor endothelial cells), and tumor targeting (of tumor cells) of anticancer drugs. Cationic liposomes have shown considerable promise in preclinical xenograft models and are poised for clinical development.     

Lipid-based drug delivery systems for cancer treatment

It is a fact that chemotherapy agents have little specificity for cancer cells, this leading to low concentrations into the tumor interstititum and severe side effects on healthy tissues. The formulation of lipid-based nanomedicines against cancer has been hypothesized to improve drug localization into the tumor tissue and to increase the anticancer efficacy of concentional drugs, while minimizing their systemic adverse effects. In this review, special attention is devoted to the analysis of the state-of-the-art in the development of lipid-based drug carriers against cancer. Specifically, the most significant in vitro and in vivo results on the use of niosomes, liposomes, and solid lipid nanoparticles are revised. It is concluded that biodistribution profiles of chemotherapy agents can be controlled by their loading to such nanoplatforms. Lipid-based nanomedicines offer an interesting approach to the delivery of anticancer drugs to brain tumors, and to reverse multi-drug resistance of cancer cells. Finally, a deep evaluation of the applicability of drug delivery strategies in the formulation of lipid-based nanoplatforms is carried out. They involve active drug targeting (including ligand-mediated delivery, and stimuli-sensitive carriers), and passive drug targeting (through the enhanced permeability and retention effect) to tumors.     

Cancer-targeted design of bioresponsive prodrug with enhanced cellular uptake to achieve precise cancer therapy

Chemical drug design based on the biochemical characteristics of cancer cells has become an important strategy for discovery of novel anticancer drugs to enhance the cancer targeting effects and biocompatibility, and decrease toxic side effects. Camptothecin (CPT) demonstrated strong anticancer activity in clinical trials but also notorious adverse effects. In this study, we presented a smart targeted delivery system (Biotin-ss-CPT) that consists of cancer-targeted moiety (biotin), a cleavable disulfide linker (S-S bond) and the active drug CPT. Biotin-ss-CPT was found to exhibit potent effects on the migration of cancer cells and induced apoptosis by induction of ROS-mediated mitochondrial dysfunction and perturbation of GSH/GPXs system, as well as activation of caspases. In vivo tumor suppression investigation including toxicity evaluation and pathology analysis, accompanied by MR images showed that Biotin-ss-CPT can be recognized specifically and selectively and taken up preferentially by cancers cells, followed by localization and accumulation effectively in tumor site, then released CPT by biological response to achieve high therapeutic effect and remarkably reduced the side effects that free CPT caused, such as liver damage, renal injury, and weight loss to realize precise cancer therapy. Taken together, our results suggest that biotinylation and bioresponsive functionalization of anticancer drugs could be a good way for the discovery of next-generation cancer therapeutics.     

Multifunctional nanomedicine platform for cancer specific delivery of siRNA by superparamagnetic iron oxide nanoparticles-dendrimer complexes

The ability of Superparamagnetic Iron Oxide (SPIO) nanoparticles and Poly(Propyleneimine) generation 5 dendrimers (PPI G5) to cooperatively provoke siRNA complexation was investigated in order to develop a targeted, multifunctional siRNA delivery system for cancer therapy. Poly(ethylene glycol) (PEG) coating and cancer specific targeting moiety (LHRH peptide) have been incorporated into SPIO-PPI G5-siRNA complexes to enhance serum stability and selective internalization by cancer cells. Such a modification of siRNA nanoparticles enhanced its internalization into cancer cells and increased the efficiency of targeted gene suppression in vitro. Moreover, the developed siRNA delivery system was capable of sufficiently enhancing in vivo antitumor activity of an anticancer drug (Cisplatin). The proposed approach demonstrates potential for the creation of targeted multifunctional nanomedicine platforms with the ability to deliver therapeutic siRNA specifically to cancer cells in order to prevent severe adverse side effects on healthy tissues and in situ monitoring of the therapeutic outcome using clinically relevant imaging techniques.     

Translocation of liposomes into cancer cells by cell-penetrating peptides penetratin and tat: a kinetic and efficacy study

Unlike conventional liposomes, sterically stabilized liposomes, with their smaller volume of distribution and reduced clearance, preferentially convey encapsulated drugs into tumor sites. Despite these improvements, intracellular delivery is hampered by the stable drug retention of the liposomes, which diminishes the efficacy of the liposomal drug. To facilitate uptake of liposomal drugs into cells, two cell-penetrating peptides, penetratin (PEN) and TAT, derived from the HIV-1 TAT protein, were studied. In contrast to control peptides, both TAT and PEN enhanced the translocation efficiency of liposomes in proportion to the number of peptides attached to the liposomal surface. A peptide number of as few as five could enhance the intracellular delivery of liposomes. The kinetics of uptake was peptide- and cell-type dependent. Intracellular accumulation of TAT-liposomes increased with incubation time, but PEN-liposomes peaked at 1 h and then declined gradually. After treatment with 1 microg/ml doxorubicin equivalents of liposome for 2 h, TAT increased the doxorubicin uptake of A431 cells by 12-fold. However, the improvement of uptake of liposomal doxorubicin was not reflected by cytotoxicity in vitro or tumor control in vivo. Our results demonstrated that merely adding CPP to a liposome encapsulating anticancer drug was inadequate in improving its antitumor activity. An additional approach to enhance the intracellular release of the encapsulated drug is obviously necessary.     

Effects of doxorubicin-encapsulating AG73 peptide-modified liposomes on tumor selectivity and cytotoxicity

Doxorubicin-encapsulating liposomal formulations, known as Doxil, have been used for the treatment of Kaposi’s sarcoma and ovarian cancer. However, there is still a need for a drug delivery system for doxorubicin that limits the treatment’s side effects, namely, mucositis and hand-and-foot syndrome. The AG73 peptide derived from the laminin α1 chain is a ligand for syndecans, and syndecan-2 is highly expressed in some cancer cells. In this study, to develop a safer and more selective liposomal formulation, we prepared doxorubicin-encapsulating AG73 peptide-modified liposomes (AG73–Dox). First, we assessed the selectivity of AG73–Dox for cancer cells, including syndecan-2 over-expressing cells, using flow cytometry and confocal microscopy. AG73–Dox showed selective cellular uptake on cancer cells and enhancement of the intracellular uptake. Next, we examined the cytotoxicity of AG73–Dox using a WST assay. AG73–Dox exhibited a higher cytotoxicity against cancer cells than other control liposomes. In addition, we showed that the antitumor efficacy of AG73–Dox in vivo was better than that of free Dox. When we examined the biodistribution of liposomes, AG73 peptide-modified liposomes (AG73-L) tended to bind to intratumoral vessels and extravasated in the tumor tissue. Thus, further optimization of AG73-L toward tumor targeting may lead to a development of a useful tool for cancer therapy.     

pH-sensitive liposomes--principle and application in cancer therapy

The purpose of this review is to provide an insight into the different aspects of pH-sensitive liposomes. The review consists of 6 parts: the first introduces different types of medications made in liposomal drug delivery to overcome several drawbacks; the second elaborates the development of pH-sensitive liposomes; the third explains diverse mechanisms associated with the endocytosis and the cytosolic delivery of the drugs through pH-sensitive liposomes; the fourth describes the role and importance of pH-sensitive lipid dioleoylphosphatidylethanolamine (DOPE) and research carried on it; the fifth explains successful strategies used so far using the mechanism of pH sensitivity for fusogenic activity; the final part is a compilation of research that has played a significant role in emphasizing the success of pH-sensitive liposomes as an efficient drug delivery system in the treatment of malignant tumours. pH-Sensitive liposomes have been extensively studied in recent years as an amicable alternative to conventional liposomes in effectively targeting and accumulating anti-cancer drugs in tumours. This research suggests that pH-sensitive liposomes are more efficient in delivering anti-cancer drugs than conventional and long-circulating liposomes due to their fusogenic property. Research focused on the clinical and therapeutic side of pH-sensitive liposomes would enable their commercial utility in cancer treatment.