Effective Delivery Strategies Research Articles

CD123/CD33 dual-antibody modified liposomes effectively target acute myeloid leukemia cells and reduce antigen-negative escape.

Most antibody-based therapies for AML target a single antigen on the surface of AML cells, which has a limited clinical benefit due to unsatisfied targeting ability and antigen-negative escape. Here we described the development and specific targeting of daunorubicin (DNR)-loaded CD123/CD33 dual-antibody modified liposome, CD123/CD33-LP-DNR. Since the majority of AML cells carries at least one of the antigens of CD123 and CD33, it is promising to treat AML using the dual-targeting agents. In this study, antibody mixture of CD123 and CD33 (1:1, molar ratio) were thiolated and coupled to Mal-PEG2000-DSPE, then the antibody-Mal-PEG2000-DSPE conjugations were inserted on the DNR-loaded PEGylated liposomes (PEG-LP-DNR) via a post insertion method to prepare CD123/CD33-LP-DNR (antibody/S100PC, molar ratio, 0.06%). The cellular uptake and cytotoxicity were evaluated in THP-1 (CD123brightCD33bright) and HL-60 (CD123dimCD33bright) cells. Compared to the unmodified liposome, CD123/CD33-LP-DNR showed higher cellular uptake which was 1.8-times and 1.6-times in both THP-1 and HL-60 cells, respectively, while the cellular uptake increased to 1.5-times only in the CD123bright cells for the single-antibody modified liposome, CD123-LP-DNR. MTT assay indicated stronger cytotoxicity of CD123/CD33-LP-DNR than CD123-LP-DNR on AML cells. The results indicated that CD123/CD33-LP-DNR might present an effective delivery strategy to enhance the targeting ability against AML cells and potentially reduce the antigen-negative escape.

Neurogenesis in Neurodegenerative Diseases: Role of MFG-E8.

Neurodegenerative diseases are devastating medical conditions with no effective treatments. Restoration of impaired neurogenesis represents a promising therapeutic strategy for neurodegenerative diseases. Milk fat globule-epidermal growth factor-factor VIII (MFG-E8) is a secretory glycoprotein that plays a wide range of cellular functions including phagocytosis of apoptotic cells, anti-inflammation, tissue regeneration, and homeostasis. The beneficial role of MFG-E8 has been shown in cerebral ischemia (stroke), neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, and traumatic brain injury. In stroke, MFG-E8 promotes neural stem cell proliferation and their migration toward the ischemic brain tissues. These novel functions of MFG-E8 are primarily mediated through its receptor αvβ3-integrin. Here, we focus on the pivotal role of MFG-E8 in protecting against neuronal diseases by promoting neurogenesis. We also discuss the mechanisms of MFG-E8-mediated neural stem/progenitor cell (NSPC) proliferation and migration, and the potential of MFG-E8 for neural stem cell niche maintenance via angiogenesis. We propose further investigation of the molecular pathways for MFG-E8 signaling in NSPC and effective strategies for MFG-E8 delivery across the blood–brain barrier, which will help develop MFG-E8 as a future drug candidate for the bedside management of neurodegenerative diseases.

Strategizing biodegradable polymeric nanoparticles to cross the biological barriers for cancer targeting.

The biological barriers in the body have been fabricated by nature to protect the body from foreign molecules. The successful delivery of drugs is limited and being challenged by these biological barriers including the gastrointestinal tract, brain, skin, lungs, nose, mouth mucosa, and immune system. In this review article, we envisage to understand the functionalities of these barriers and revealing various drug-loaded biodegradable polymeric nanoparticles to overcome these barriers and deliver the entrapped drugs to cancer targeted site. Apart from it, tissue-specific multifunctional ligands, linkers and transporters when employed imparts an effective active delivery strategy by receptor-mediated transcytosis. Together, these strategies enable to deliver various drugs across the biological membranes for the treatment of solid tumors and malignant cancer.

Update on Gaseous Signaling Molecules Nitric Oxide and Hydrogen Sulfide: Strategies to Capture their Functional Activity for Human Therapeutics.

Discovery of the production of gaseous molecules, such as nitric oxide and hydrogen sulfide, within the human body began a new concept in cellular signaling. Over the past 30 years, these molecules have been investigated and found to have extremely important beneficial effects in numerous chronic diseases. Gaseous signaling molecules that diffuse in three dimensions apparently contradict the selectivity and specificity afforded by normal ligand receptor binding and activation. This new concept has also created hurdles in the development of safe and efficacious drug therapy based on these molecules. Mechanisms involving formation of more stable intermediates and second messengers allow for new strategies for safe and effective delivery of these molecules for human disease. The purpose of this review is to highlight the biologic effects of nitric oxide and hydrogen sulfide, their seemingly indistinguishable effects, and how these molecules can be safely harnessed for drug development and precursors or substrates administered for human consumption through applied physiology.

Liposomal formulation and pharmacokinetic study of CPD409, a novel sodium channel blocker

CPD409 is a novel sodium channel blocker for pain control in chemotherapy-induced peripheral neuropathy with a very poor water solubility of less than 10 μg/mL. The aim of this study is to improve the aqueous solubility of CPD409 by using inclusion complexes with β-cyclodextrin (β-CD) and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD). The inclusion complexes were prepared by two different methods; common solvent evaporation (CSE) and freeze-drying (FD) method. The phase solubility study indicated that HP-β-CD showed 3-times higher formation constant with CPD409 than β-CD. Inclusion complexes at a molar ratio of 1:2 increased the solubility of CPD409 by 130 times when compared with pure CPD409. The physicochemical characterization of the prepared formulation confirmed the formation of CPD409/HP-β-CD inclusion complexes. In dissolution study, inclusion complexes at a molar ratio of 1:2 released 70% of CPD409 but CSE method showed more rapid dissolution profile than FD method. Pharmacokinetic study also showed an increased bioavailability in 1:2 formulation compared to pure CPD409. In conclusion, inclusion complexes of CSE and FD method at a molar ratio of 1:2 showed increased solubility, dissolution rate, and bioavailability of CPD409. Therefore, complexation of CPD409 with HP-β-CD using CSE and FD method at a molar ratio 1:2 can be promising strategy for effective oral delivery.

Cancer cell membrane cloaking nanoparticles for targeted co-delivery of doxorubicin and PD-L1 siRNA

Nanoparticles coated with cell membranes have been garnering growing attention due to their homologous binding capability of membrane molecules and consequent self-recognition by their source cells. In the present study, we report on the construction of doxorubicin and PD-L1 siRNA-loaded PLGA nanoparticles and their biological functionalization by cancer cell-derived membrane cloaking. The resulting cancer cell membrane-coated nanoparticles (CCMNPs) presented a core-shell nanostructure with highly specific self-recognition affinity to the homotypic cells, which can be attributed to the transference of cell adhesion molecules with homotypic binding properties. These findings facilitate the application of this bioinspired strategy for effective delivery of siRNA and precise tumour therapy.

Liposome delivery system and treatment of Alzheimer's diease

Alzheimer's disease is a common disease among the elderly. It seriously affects the quality of life of patients. There is still no effective treatment. The existence of blood-brain barrier further limits the efficacy of therapeutic drugs. As a highly safe nano-carrier, liposomes can not only carry drugs into the brain, but also have the advantages of reducing toxicity and side effects. Therefore, liposomes are promising in the treatment of Alzheimer's disease. This paper summarized the application of different types and functions of liposomes in various therapeutic drugs for Alzheimer's disease, aiming to provide an effective delivery strategy for the treatment of Alzheimer's disease. Key words: Alzheimer's disease; Liposome; Blood-brain barrier; Nanomedicine

PO 8426 DELIVERY OF POST-DISCHARGE MALARIA CHEMOPREVENTION (PMC) WITH DIHYDROARTEMESININ-PIPERAQUINE FOR MANAGEMENT OF CHILDREN WITH SEVERE ANAEMIA IN MALAWI

BackgroundChildren hospitalised with severe anaemia in Africa are at high risk of readmission or death within 6 months after discharge. No strategy addresses this post-discharge period. In Malawi, 3 months of post-discharge malaria chemoprevention (PMC) with monthly 3 day courses of artemether-lumefantrine (AL) in children with severe malarial anaemia prevented 31% of deaths and readmissions. There is now a need to design and evaluate an effective delivery strategy for PMC.MethodsThis is a cluster-randomised trial whose primary objective is to determine the optimum PMC delivery strategy by comparing community versus health facility-based strategies with the aim to inform policy. Convalescent children under 5 years old, weighing >5 kg, admitted with severe anaemia and clinically stable are included. All children received dihydroartemisinin-piperaquine 2, 6 and 10 weeks after discharge, either: 1) at discharge with SMS reminder; 2) at discharge without an SMS reminder; 3) at discharge and community health worker reminder; 4) at the hospital with an SMS reminder; or 5) at the hospital without an SMS reminder. The primary outcome measure is uptake of courses of PMC drugs. Children will be followed up for 15 weeks. The sample size is 75 children per arm (375 total).ResultsThe study has nearly completed enrollment and preliminary data analysis is in progress. We expect to identify the most effective, cost-effective, acceptable and feasible strategy for delivering intermittent preventive therapy post-discharge for management of severe anaemia in under-five children.ConclusionThe findings of this study will be presented; they address the knowledge gap regarding the potentially preventable component of the burden that occurs after discharge from hospital, and inform the optimal delivery strategy for PMC.

Microlearning: Quick and Meaningful Snippets for Training Solutions

ملخص البحث: يؤدي التقدم في تكنولوجيا المعلومات، مع التغييرات في المجتمع إلى إيجاد نماذج جديدة للتدريب. ينظر إلى على أنها برامج فعالة من حيث التكلفة تعمل كتدريب سريع وذي مغزى. وتصنف إلى معلوماتية و تعليمية. تستخدم المقتطفات المعلوماتية لتوفير معلومات سريعة للجمهور المستهدف، في حين يمكن النظر إلى المقتطفات التعليمية باعتبارها كائنات تعلم استخدمت بالفعل لتعليم شيء ما. ويمكن استخدام كلا النوعين من المقتطفات كعوامل تعزيز لعالم التدريب. يمكن استخدام المقتطفات كحلول تدريبية سريعة وفعالة من حيث التكلفة وأيضا كإضافات لحلول التدريب القائمة. وفي ضوء أنواع المحتوى، يمكن تطوير أنماط التعلم الخاصة بالجمهور المستهدف والقدرات المؤسسية لمنظمة ما، والاستراتيجيات الفعالة لتقديم التدريب، والعائد المرتفع على الاستثمار باستخدام إطار التعلم المرن. يستعرض منهج التصميم الواقعي المستخدم في هذه الورقة بصورة شاملة جميع مراحل عملية تطوير مقتطفات التدريب في ضوء القضايا الحرجة والمتضمنة الفئات الثمانية للإطار. باستخدام هذا المدخل، يمكن للمؤسسات تلقي توصيات لضبط تخصيص الموارد. إن نتائج استخدام المقتطفات المصممة بشكل جيد، وذات التكلفة المنخفضة، والمعززة للسلوك، تسهم في تحقيق التغيير الناجح للسلوك وتحسين الأداء للمتدربين. الكلمات الدلالية: التعلم المصغر، مقتطفات، حلول التدريب.

Advances in CRISPR/Cas9 Technology for in Vivo Translation.

Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) technology has revolutionized therapeutic gene editing by providing researchers with a new method to study and cure diseases previously considered untreatable. While the full range and power of CRISPR technology for therapeutics is being elucidated through in vitro studies, translation to in vivo studies is slow. To date there is no totally effective delivery strategy to carry CRISPR components to the target site in vivo. The complexity of in vivo delivery is furthered by the number of potential delivery methods, the different forms in which CRISPR can be delivered as a therapeutic, and the disease target and tissue type in question. There are major challenges and limitations to delivery strategies, and it is imperative that future directions are guided by well-conducted studies that consider the full effect these variables have on the eventual outcome. In this review we will discuss the advances of the latest in vivo CRISPR/Cas9 delivery strategies and highlight the challenges yet to be overcome.

Effective library services for children and young people in public libraries:A developing structured review

Public libraries play fundamental roles in providing children and young people with free and open access to knowledge, especially in developing countries like Nigeria. Toddlers come for story times, teachers and day care providers bring groups of children to find books and information, to be instructed in information literacy skills, and to hear stories. School children drop in for after-school programming or homework assistance. Hence the role of public libraries in the life of children and young people cannot be overemphasized. This paper focuses on different innovative services and programmes in public libraries for young people in the digital age; library services for children and young people and strategies for effective library service delivery. It concludes by recommending that Public Library should make a concerted effort to improve its collections, resources and services in other to meet the ever increasing need of children and young people. Keywords: Public Library, Library use, Library Services, Children and Young people.

Orally Delivered Antisense Oligodeoxyribonucleotides of TNF‐α via Polysaccharide‐Based Nanocomposites Targeting Intestinal Inflammation

Tumor necrosis factor alpha (TNF-α) is usually regarded as a potential target for inflammatory bowel disease therapy. Herein, a promising strategy for effective delivery of phosphorothioated antisense oligodeoxyribonucleotide of TNF-α (PS-ATNF-α), targeting the intestinal inflammation based on the interaction of the single chain of triple helical β-glucan (s-LNT) with poly-deoxyadenylic acid [poly(dA)], and the colon-specific degradation of chitosan-alginate (CA) hydrogel, is reported. The target gene of PS-ATNF-α, with a poly(dA) tail through a disulfide bond (-SS-), interacts with s-LNT to form a rod-like nanocomposite of s-LNT/poly(dA)-SS-PS-ATNF-α, which significantly inhibits lipopolysaccharide (LPS)-induced TNF-α at the protein level by 38.2% and mRNA level by 48.9% in RAW264.7 macrophages. The nanocomposites carried by the CA hydrogel with the loading amount of 83.5% are then orally administered and specifically released to the inflamed intestine, followed by internalization into intestinal cells such as macrophages, to reduce TNF-α production by 36.4% and dextran sulfate sodium-induced inflammation by decreasing myeloperoxidase and malondialdehyde. This study defines a new strategy for the oral delivery of antisense oligonucleotides to attenuate inflammatory response, demonstrating a notable potential for clinical applications in intestine-inflammation-targeted therapy.

Service Providers' Perception of Barriers to Access Mental Health Services

Background: The literature shows that mental health services are yet not adequate and whatever is available is underutilized in India. The aim of the study was to identify the available mental health services; barriers to utilize and deliver mental health service and explore the strategies for effective delivery of mental health services. Methodology: The Expert Interview and Key Informant Interview were the methods of data collection. A standardized script for conducting the interviews was developed based on literature review and discussion with experienced qualitative researchers as per the objectives of the study. Results: The main themes identified under the study were - mental health services, services & facilities under District Mental Health Programme, mental health services in primary health centres, barriers to utilizing mental health services, policy-level barriers to provide mental health services, recommendations and suggestions from service providers to improve mental health service system. Conclusion: There are multiple barriers, which need to be addressed effectively. There is a need to create a network among all stakeholders. Keywords: Mental health service, district mental health programme, India

Innovative approaches reaching underserved and rural communities to improve epilepsy care: A review of the methodology of the Connectors Project

ObjectiveThe Connectors Project, a collaboration between the Epilepsy Foundation and UCB Pharma, was a multiyear project designed to improve epilepsy care in underserved communities. A core objective of the Connectors Project was to pilot new and innovative approaches to epilepsy awareness and education in rural and underserved areas, including standardized curricula for healthcare providers and patients. MethodsA series of consensus conferences explored opportunities and barriers to epilepsy care throughout the United States including access to local Epilepsy Foundations, neurologists, and epilepsy centers. Data from QuintilesIMS™ were examined for access to newer antiepileptic drugs (AEDs)—a proxy for quality of epilepsy care—in different regions. State factors (e.g., local epilepsy foundation office, access to newer vs. older AEDs, and geographic density and diversity) were used in selecting four states as examples of rural and underserved areas to pilot the awareness and educational programs. For each state, a work team assessed challenges and opportunities, tailored educational curricula, and developed strategies for effective delivery of the educational programs. Interventions were held between June 2016 and June 2017. Interventions consisted of outreach and awareness programs, in-person health education to healthcare providers and patients/families, and digital health education. ResultsMichigan, Nevada, Oklahoma, and West Virginia were identified as pilot states representing geographically diverse areas, ranging from a state with a large high-density population center with several epilepsy centers and a local Epilepsy Foundation office (Michigan) to a state with predominately rural areas and a few small urban cores, two epilepsy centers, and no in-state Epilepsy Foundation office (West Virginia). State work teams tailored interventions and examined options for type, intent, ease of use, and impact. All states implemented outreach and awareness initiatives and in-person health education for patients and healthcare providers; use of digital health education was variable. Measurement of the interventions was agreed to be performed by the use of patient and physician surveys and reevaluation of data from QuintilesIMS for access to newer AEDs. ConclusionLocal Epilepsy Foundation offices successfully connected healthcare providers in rural and underserved areas to epilepsy education designed to enhance quality care in epilepsy. Educational opportunities for people with epilepsy and their families addressed critical gaps in accessing quality epilepsy care and self-management. Tailored and innovative educational approaches can be used to increase awareness levels and to overcome geographic challenges in reaching underserved populations. Relationship building and repeated, consistent engagement with healthcare providers and patients can assist in improving communication and self-management skills among patients with epilepsy.

Ultra-long-acting removable drug delivery system for HIV treatment and prevention

Non-adherence to medication is an important health care problem, especially in the treatment of chronic conditions. Injectable long-acting (LA) formulations of antiretrovirals (ARVs) represent a viable alternative to improve adherence to HIV/AIDS treatment and prevention. However, the LA-ARV formulations currently in clinical trials cannot be removed after administration even if adverse events occur. Here we show an ultra-LA removable system that delivers drug for up to 9 months and can be safely removed to stop drug delivery. We use two pre-clinical models for HIV transmission and treatment, non-human primates (NHP) and humanized BLT (bone marrow/liver/thymus) mice and show a single dose of subcutaneously administered ultra-LA dolutegravir effectively delivers the drug in both models and show suppression of viremia and protection from multiple high-dose vaginal HIV challenges in BLT mice. This approach represents a potentially effective strategy for the ultra-LA drug delivery with multiple possible therapeutic applications.

Preparation of Reduction-Responsive Camptothecin Nanocapsules by Combining Nanoprecipitation and In Situ Polymerization for Anticancer Therapy.

Stimuli-responsive systems for controlled drug release have been extensively explored in recent years. In this work, we developed a reduction-responsive camptothecin (CPT) nanocapsule (CPT-NC) by combining nanoprecipitation and in situ polymerization using a polymerized surface ligand and a disulfide bond-containing crosslinker. Dissolution rate studies proved that the CPT-NCs have robust drug-release profiles in the presence of glutathione (GSH) owing to the division of the disulfide bond crosslinker which triggers the collapse of the polymer layer. Furthermore, the in vitro investigations demonstrated that the CPT-NCs exhibited a high-cellular uptake efficiency and cytotoxicity for cancer cells of squamous cell carcinoma (SCC-15). Our approach thus presents an effective intracellular drug delivery strategy for anticancer therapy.

Delivery strategies for malaria chemoprevention with monthly dihydroartemisinin-piperaquine for the post-discharge management of severe anaemia in children aged less than 5\xa0years old in Malawi: a protocol for a cluster randomized trial

BackgroundChildren initially hospitalized with severe anaemia in Africa are at high risk of readmission or death within 6 months after discharge. No intervention strategy specifically protects children during the post-discharge period. Recent evidence from Malawi shows that 3 months of post-discharge malaria chemoprevention (PMC) with monthly treatment with artemether-lumefantrine in children with severe malarial anaemia prevented 31% of deaths and readmissions. While a confirmatory multi-centre trial for PMC with dihydroartemisinin-piperaquine is on going in Kenya and Uganda, there is a need to design and evaluate an effective delivery strategy for this promising intervention.MethodsThis is a cluster-randomized trial with 5 arms, each representing a unique PMC delivery strategy. Convalescent children aged less than 5 years and weighing more than 5 kg admitted with severe anaemia and clinically stable are included. All eligible children will receive dihydroartemisinin-piperaquine at 2, 6 and 10 weeks after discharge either: 1) in the community without an SMS reminder; 2) in the community with an SMS reminder; 3) in the community with a community health worker reminder; 4) at the hospital with an SMS reminder; or 5) at the hospital without an SMS reminder. For community-based strategies (1, 2 and 3), mothers will be given all the PMC doses at the time of discharge while for hospital-based strategies (4 and 5) mothers will be required to visit the hospital each month. Each arm will consist of 25 clusters with an average of 3 children per cluster giving approximately 75 children and will be followed up for 15 weeks. The primary outcome measure is uptake of complete courses of PMC drugs.DiscussionThe proposed study will help to identify the most effective, cost-effective, acceptable and feasible strategy for delivering malaria chemoprevention for post-discharge management of severe anaemia in under-five children in the Malawian context. This information is important for policy decision in the quest for new strategies for malaria control in children in similar contexts.Trial registrationClinicalTrials.gov: NCT02721420. Protocol registered on 29 March 2016.The study was not retrospectively registered but there was a delay between date of submission and the date it first became available on the registry.

Acceleration of Diabetic Wound Regeneration using an In Situ-Formed Stem-Cell-Based Skin Substitute.

Chronic diabetic ulcers are a common complication in patients with diabetes, often leading to lower limb amputations and even mortality. Stem cells have shown promise in promoting cutaneous wound healing by modulating inflammation, angiogenesis, and re-epithelialization. However, more effective delivery and engraftment strategies are needed to prolong transplanted stem cell lifespan and their pro-healing functions in a chronic wound environment to improve skin regeneration. In this study, an injectable poly(ethylene glycol) (PEG)-gelatin-based hydrogel system is examined to create a functional stem cell niche for the delivery of adipose-derived stem cells (ASCs) into diabetic wounds. Human ASCs are encapsulated into the in situ crosslinked hydrogels and cultured in a 3D topography. The encapsulated cells are well attached and spread inside the hydrogels, retaining viability, proliferation, and metabolic activity up to three weeks in vitro. Allogeneic ASCs are delivered to diabetic wounds by this hydrogel vehicle. It is found that stem cell retention is significantly improved in vivo with vehicle-mediated delivery. The ASC-hydrogel-based treatment decreases inflammatory cell infiltration, enhances neovascularization, and remarkably accelerates wound closure in diabetic mice. Together, these findings suggest this conveniently-applicable ASC-hydrogel-based skin substitute provides a promising potential for the treatment of chronic diabetic wounds.

A Glutamine-Rich Carrier Efficiently Delivers Anti-CD47 siRNA Driven by a "Glutamine Trap" To Inhibit Lung Cancer Cell Growth.

It is not efficient enough using the current approaches for tumor-selective drug delivery based on the EPR effect and ligand-receptor interactions, and they have largely failed to translate into the clinic. Therefore, it is urgent to explore an enhanced strategy for effective delivery of anticancer agents. Clinically, many cancers require large amounts of glutamine for their continued growth and survival, resulting in circulating glutamine extraction by the tumor being much greater than that for any organs, behaving as a "glutamine trap". In the present study, we sought to elucidate whether the glutamine-trap effect could be exploited to deliver therapeutic agents to selectively kill cancer cells. Here, a macromolecular glutamine analogue, glutamine-functionalized branched polyethylenimine (GPI), was constructed as the carrier to deliver anti-CD47 siRNA for the blockage of CD47 "don't eat me" signals on cancer cells. The GPI/siRNA glutamine-rich polyplexes exhibited remarkably high levels of cellular uptake by glutamine-dependent lung cancer cells, wild-type A549 cells (A549WT), and its cisplatin-resistant cells (A549DDP), specifically under glutamine-depleted conditions. It was noted that the glutamine transporter ASCT2 was highly expressed both on A549WT and A549DDP but with almost no expression in normal human lung fibroblasts cells. Inhibition of ASCT2 significantly prevented the internalization of GPI polyplexes. These findings raised the intriguing possibility that the glutamine-rich GPI polyplexes utilize the ASCT2 pathway to selectively facilitate their cellular uptake by cancer cells. GPI further delivered anti-CD47 siRNA efficiently both in vitro and in vivo to downregulate the intratumoral mRNA and protein expression levels of CD47. CD47 functions as a "don't eat me" signal and binds to the immunoreceptor SIRPα inducing evasion of phagocytic clearance. GPI/anti-CD47 siRNA polyplexes achieved significant antitumor activities both on A549WT and A549DDP tumor-bearing nude mice. Notably, it had no adverse effect on CD47-expressing red blood cells and platelets, likely because of selective delivery. Therefore, the glutamine-rich carrier GPI driven by the glutamine-trap effect provides a promising new strategy for designing anticancer drug delivery systems.

Paclitaxel delivered by CD44 receptor-targeting and endosomal pH sensitive dual functionalized hyaluronic acid micelles for multidrug resistance reversion

The drug efflux mediated by P-glycoprotein (P-gp) transporter is a major factor responsible for multidrug resistance (MDR) of paclitaxel (PTX). The efficient intracellular PTX delivery is a promising strategy for overcoming the MDR of tumor cells. A CD44 receptor targeting and endosome-pH sensitive dual functionalized hyaluronic acid-deoxycholic acid-histidine (HA-DOCA-His) micellar formulation was developed to overcome MDR, and a CD44 receptor targeting hyaluronic acid-deoxycholic acid (HA-DOCA) micelles was used as a comparison. Compared with Taxol solution and HA-DOCA micelles, the cytotoxicity of PTX loaded in HA-DOCA-His micelles against drug-resistant tumor cells was improved significantly and possessed superior MDR-overcoming performance; this phenomenon is due to the increased intracellular PTX delivery by CD44 receptor-mediated endocytosis pathway and endosome-pH sensitivity-mediated PTX triggering release. Upon pharmacokinetic study, PTX/HA-DOCA-His micelles demonstrated longer blood circulation time, larger AUC, decreased Vd and CL than the Taxol solution. More importantly, PTX/HA-DOCA-His micelles were more effective in tumor growth inhibition in MCF-7/Adr tumor-bearing mice compared with PTX/HA-DOCA micelles and Taxol solution. Dual targeting strategy-functionalized HA-DOCA-His micelles demonstrated excellent MDR-reversing ability for therapeutic efficacy and improvement on MDR tumors, thereby providing an effective targeting strategy for PTX delivery of nano-drug delivery system in MDR cancer chemotherapy.