Adverse Effects Of Cancer Therapy Research Articles

Rational design and latest advances of codelivery systems for cancer therapy.

Current treatments have limited effectiveness in treating tumors. The combination of multiple drugs or treatment strategies is widely studied to improve therapeutic effect and reduce adverse effects of cancer therapy. The codelivery system is the key to realize combined therapies. It is necessary to design and construct different codelivery systems in accordance with the variable structures and properties of cargoes and vectors. This review presented the typical design considerations about codelivery vectors for cancer therapy and described the current state of codelivery systems from two aspects: different types of vectors and collaborative treatment strategies. The commonly used loading methods of cargoes into the vectors, including physical and chemical processes, are discussed in detail. Finally, we outline the challenges and perspectives about the improvement of codelivery systems.

Adverse cardiac effects of cancer therapies: cardiotoxicity and arrhythmia.

Remarkable progress has been made in the development of new therapies for cancer, dramatically changing the landscape of treatment approaches for several malignancies and continuing to increase patient survival. Accordingly, adverse effects of cancer therapies that interfere with the continuation of best-possible care, induce life-threatening risks or lead to long-term morbidity are gaining increasing importance. Cardiovascular toxic effects of cancer therapeutics and radiation therapy are the epitome of such concerns, and proper knowledge, interpretation and management are needed and have to be placed within the context of the overall care of individual patients with cancer. Furthermore, the cardiotoxicity spectrum has broadened to include myocarditis with immune checkpoint inhibitors and cardiac dysfunction in the setting of cytokine release syndrome with chimeric antigen receptor T cell therapy. An increase in the incidence of arrhythmias related to inflammation such as atrial fibrillation can also be expected, in addition to the broadening set of cancer therapeutics that can induce prolongation of the corrected QT interval. Therefore, cardiologists of today have to be familiar not only with the cardiotoxicity associated with traditional cancer therapies, such as anthracycline, trastuzumab or radiation therapy, but even more so with an ever-increasing repertoire of therapeutics. This Review provides this information, summarizing the latest developments at the juncture of cardiology, oncology and haematology.

Therapy-Induced Senescence: An "Old" Friend Becomes the Enemy.

For the past two decades, cellular senescence has been recognized as a central component of the tumor cell response to chemotherapy and radiation. Traditionally, this form of senescence, termed Therapy-Induced Senescence (TIS), was linked to extensive nuclear damage precipitated by classical genotoxic chemotherapy. However, a number of other forms of therapy have also been shown to induce senescence in tumor cells independently of direct genomic damage. This review attempts to provide a comprehensive summary of both conventional and targeted anticancer therapeutics that have been shown to induce senescence in vitro and in vivo. Still, the utility of promoting senescence as a therapeutic endpoint remains under debate. Since senescence represents a durable form of growth arrest, it might be argued that senescence is a desirable outcome of cancer therapy. However, accumulating evidence suggesting that cells have the capacity to escape from TIS would support an alternative conclusion, that senescence provides an avenue whereby tumor cells can evade the potentially lethal action of anticancer drugs, allowing the cells to enter a temporary state of dormancy that eventually facilitates disease recurrence, often in a more aggressive state. Furthermore, TIS is now strongly connected to tumor cell remodeling, potentially to tumor dormancy, acquiring more ominous malignant phenotypes and accounts for several untoward adverse effects of cancer therapy. Here, we argue that senescence represents a barrier to effective anticancer treatment, and discuss the emerging efforts to identify and exploit agents with senolytic properties as a strategy for elimination of the persistent residual surviving tumor cell population, with the goal of mitigating the tumor-promoting influence of the senescent cells and to thereby reduce the likelihood of cancer relapse.

Kinase-independent inhibition of cyclophosphamide-induced pathways protects the ovarian reserve and prolongs fertility

Premature ovarian failure and infertility are adverse effects of cancer therapies. The mechanism underlying chemotherapy-mediated depletion of the ovarian reserve remains unclear. Here, we aim to identify the signaling pathways involved in the loss of the ovarian reserve to prevent the damaging effects of chemotherapy. We evaluated the effects of cyclophosphamide, one of the most damaging chemotherapeutic drugs, against follicle reserve. In vivo studies showed that the cyclophosphamide-induced loss of ovarian reserve occurred through a sequential mechanism. Cyclophosphamide exposure induced the activation of both DNAPK-γH2AX-checkpoint kinase 2 (CHK2)-p53/TAp63α isoform and protein kinase B (AKT)-forkhead box O3 (FOXO3a) signaling axes in the nucleus of oocytes. Concomitant administration of an allosteric ABL inhibitor and cyclophosphamide modulated both pathways while protecting the ovarian reserve from chemotherapy assaults. As a consequence, the fertility of the treated mice was prolonged. On the contrary, the administration of an allosteric ABL activator enhanced the lethal effects of cyclophosphamide while shortening mouse fertility. Therefore, kinase-independent inhibition may serve as an effective ovarian-protective strategy in women under chemotherapy.

Gut Microbiota Shapes the Efficiency of Cancer Therapy.

Systems biology provides an opportunity to discover the role that gut microbiota play in almost all aspects of human health. Existing evidence supports the hypothesis that gut microbiota is closely related to the pharmacological effects of chemical therapy and novel targeted immunotherapy. Gut microbiota shapes the efficiency of drugs through several key mechanisms: metabolism, immunomodulation, translocation, enzymatic degradation, reduction of diversity, and ecological variability. Therefore, gut microbiota have emerged as a novel target to enhance the efficacy and reduce the toxicity and adverse effects of cancer therapy. There is growing evidence to show that cancer therapy perturbs the host immune response and results in dysbiosis of the immune system, which then influences the efficiency of the therapy. Studies suggest that gut microbes play a significant role in cancer therapy by modulating drug efficacy, abolishing the anticancer effect, and mediating toxicity. In this review, we outline the role of gut microbiota in modulating cancer therapy and the implications for improving the efficacy of chemotherapy and immunotherapy in clinical practice. We also summarize the current limitations of the safety and effectiveness of probiotics in cancer therapies such as personalized cancer therapy.

Genipin Enhances the Therapeutic Effects of Oxaliplatin by Upregulating BIM in Colorectal Cancer.

Despite an increase in the survival rate of patients with cancer owing to the use of current chemotherapeutic agents, adverse effects of cancer therapies remain a concern. Combination therapies have been developed to increase efficacy, reduce adverse effects, and overcome drug resistance. Genipin is a natural product derived from Gardenia jasminoides, which has been associated with anti-inflammatory, anti-angiogenic, and anti-proliferative effects; hypertension; and anti-ischemic brain injuries. However, the enhancement of oxaliplatin sensitivity by genipin remains unexplored. Our study showed that a combination of genipin and oxaliplatin exerts synergistic antitumor effects in vitro and in vivo in colorectal cancer cell lines through the reactive oxygen species (ROS)/endoplasmic reticulum (ER) stress/BIM pathway. Importantly, the combination did not affect normal colon cells. BIM knockdown markedly inhibited apoptosis induced by the combination. In addition, genipin induced ROS by inhibiting superoxide dismutase 3 activity. These findings suggest that genipin may be a novel agent for increasing the sensitivity of oxaliplatin against colorectal cancer. The combination of oxaliplatin and genipin hold significant therapeutic potential with minimal adverse effects.

The skeletal impact of cancer therapies.

Both cancer and therapies used in the treatment of cancer can have significant deleterious effects on the skeleton, increasing the risks for both bone loss and fracture development. While advancements in cancer therapies have resulted in enhanced cancer survivorship for patients with many types of malignancies, it is increasingly recognized that efforts to reduce bone loss and limit fractures must be considered for nearly all patients undergoing cancer therapy in order to diminish the anticipated future skeletal consequences. To date, most studies examining the impact of cancer therapies on skeletal outcomes have focused on endocrine-associated cancers of the breast and prostate, with more recent advances in our understanding of bone loss and fracture risk in other malignancies. Pharmacologic efforts to limit the adverse effects of cancer therapies on bone have nearly universally employed anti-resorptive approaches, although studies have frequently relied on surrogate outcomes such as changes in bone mineral density or bone turnover markers, rather than on fractures or other skeletal-related events, as primary study endpoints. Compounding current deficiencies for the provision of optimal care is the recognition that despite clearly written and straightforward society-based guidelines, vulnerable eligible patients are very often neither identified nor provided with appropriate treatments to limit the skeletal impact of their cancer therapies.

MiR-212/132 Cluster Modulation Prevents Doxorubicin-Mediated Atrophy and Cardiotoxicity

Improved therapy of cancer has significantly increased the lifespan of patients. However, cancer survivors face an increased risk of cardiovascular complications due to adverse effects of cancer therapies. The chemotherapy drug doxorubicin is well known to induce myofibril damage and cardiac atrophy. Our aim was to test potential counteracting effects of the pro-hypertrophic miR-212/132 family in doxorubicin-induced cardiotoxicity. Invitro, overexpression of the pro-hypertrophic miR-212/132 cluster in primary rodent and human iPSC-derived cardiomyocytes inhibited doxorubicin-induced toxicity. Next, a disease model of doxorubicin-induced cardiotoxicity was established in male C57BL/6N mice. Mice were administered either adeno-associated virus (AAV)9-control or AAV9-miR-212/132 to achieve myocardial overexpression of the miR-212/132 cluster. AAV9-mediated overexpression limited cardiac atrophy by increasing left ventricular mass and wall thickness, decreased doxorubicin-mediated apoptosis, and prevented myofibril damage. Based on a transcriptomic profiling we identified fat storage-inducing transmembrane protein 2 (Fitm2) as a novel target and downstream effector molecule responsible, at least in part, for the observed miR-212/132 anti-cardiotoxic effects. Overexpression of Fitm2 partially reversed the effects of miR-212/132. Overexpression of the miR-212/132 family reduces development of doxorubicin-induced cardiotoxicity and thus could be a therapeutic entry point to limit doxorubicin-mediated adverse cardiac effects.

Dorsal root ganglion explants derived from chemotherapy-treated mice have reduced neurite outgrowth in culture

Chemotherapy-induced peripheral neuropathy (CIPN) is a severe and debilitating adverse effect of cancer therapy that results from treatment with neurotoxic agents. Although chemotherapy treatment has been shown to inhibit neurite outgrowth from dorsal root ganglion (DRG) neurons in vitro, evidence for this effect in vivo is lacking. In this study, we investigated whether chemotherapy treatment in mice alters the capacity for axonal outgrowth from ex vivo cultured DRG explants. Using a neurite outgrowth assay, we demonstrated that DRG explants isolated at day 30 from mice treated with 6 cycles of paclitaxel, or 12 cycles of oxaliplatin showed a significant reduction in neurite outgrowth as compared to DRG explants from control vehicle-treated mice. DRGs that were isolated at day 90 showed recovery of the neurite outgrowth, and no significant differences were detected in comparison to vehicle controls. These results are corroborated with an in vitro model, whereby direct application of oxaliplatin and paclitaxel dose-dependently reduced neurite outgrowth of DRG explants. In conclusion, our results show that the effect of paclitaxel and oxaliplatin on the structural plasticity of DRG is retained ex vivo (for at least 30 days) and suggest the use of DRG explants derived from chemotherapy-treated mice as an efficient method to investigate the mechanisms underlying CIPN and test for possible therapeutic targets.

Evaluation and Treatment of a Patient With Recurrent Stroke in the Setting of Active Malignancy.

Evaluation and Treatment of a Patient With Recurrent Stroke in the Setting of Active Malignancy.

Exploratory Investigation of Early Biomarkers for Chronic Fatigue in Prostate Cancer Patients Following Radiation Therapy.

Fatigue is one of the most debilitating adverse effects of cancer therapy. Identifying biomarkers early during cancer therapy may help us understand the biologic underpinnings of the persistence of fatigue following therapy. We aimed to identify early biomarkers of fatigue by examining correlations of levels of cytokines during external beam radiation therapy (EBRT) with persistence of fatigue 1 year following treatment completion in men with nonmetastatic prostate cancer (NM-PC). A sample of 34 men with nonmetastatic prostate cancer scheduled to receive EBRT were followed up at baseline (T1), midpoint of EBRT (T2), and 1 year following EBRT (T3). Demographic and clinical data were obtained by chart review. The Functional Assessment of Cancer Therapy-Fatigue was administered to measure fatigue levels. Plasma cytokine levels were determined at T1 and T2 using the Bio-Rad Bio-Plex Cytokine Assay Kits. Significant correlations were observed between levels of interleukin 2 (IL-3), IL-8, IL-9, IL-10, IL-16, interferon γ-induced protein 10, interferon α2, interferon γ, and stromal cell-derived factor 1α at T2 with worsening of fatigue from T1 to T3. Immunological changes prior to chronic fatigue development may reflect the long-term response to radiation therapy-induced damage. Early biomarkers for chronic fatigue related to cancer therapy will help advance our understanding of the etiology of this distressing symptom and will help nurses identify patients at risk of developing chronic fatigue after cancer treatment. This information will also aid in patient education, as well as symptom management.

Cardiovascular Toxicities of Small Molecule Tyrosine Kinase Inhibitors: An Opportunity for Systems-Based Approaches.

Once universally considered a rapidly fatal condition, cancer has increasingly become a chronic medical condition and comorbidities and adverse effects of cancer therapies have become increasingly significant. One of the leading advancements that has gained traction for the treatment of a variety of malignancies is the class of small molecule tyrosine kinase inhibitors (TKIs). Although, in many aspects revolutionary, TKIs have their own profile of side effects, including cardiovascular side effects, the most common being hypertension (HTN), congestive heart failure, corrected QT (QTc) prolongation, and instances of premature coronary heart disease. Herein, we describe the mechanisms of small TKI-induced cardiovascular toxicity and related intracellular signaling. In particular, systems-based approaches to the understanding of small TKI-induced cardiovascular toxicity are addressed. The pathophysiology of synergic cardiovascular toxicity from TKIs, anthracyclines, and monoclonal antibodies (e.g., trastuzumab, bevacizumab) is illustrated. Finally, recommendations are made for implementing systems medicine in clinical practice, for individualized cardiovascular wellness after cancer therapy.

Cardiovascular Toxicity of Bevacizumab in Long-term Survival of Recurrent Ovarian Cancer: A Case Report

Introduction: Bevacizumab has been shown to improve progression-free survival in women with ovarian cancer in multiple clinical trials. Cardiovascular toxicity is reported in the case of a long term survivor of recurrent ovarian cancer. Case Report: A 47-year-old woman was diagnosed as stage IIIC, Grade 3 endomitriod adenocarcinoma of the ovary. She had been treated with 4 debulking surgeries and 6 different chemotherapy regimens for 9 years. However, remission diminished over this time period to only one month. Bevacizumab was administrated with additional chemotherapies, and prolonged survival was demonstrated over the next 5 years, including ongoing remission of 18 months to date. New onset hypertension was developed at the 10th month of bevacizumab treatment, and proteinuria was found at the 12th month. Patient presented symptoms of coronary artery disease during the 31th month of bevacizumab treatment, and was soon treated with 4 stents, whereby symptoms resolved. After the 36th month of bevacizumab, the patient had non ST elevated myocardial infarction and peripheral vascular disease. Bevacizumab was terminated thereafter. In the following 18 months, the patient was treated with angioplasty 2 times for coronary artery occlusion, and with an additional stent. This was followed with coronary artery bypass graft. She also had an angioplasty for right femoral artery stenosis. Throughout most of the 14 year disease course, the patient maintained a good quality of life. As patients achieve long term survival from bevacizumab treatment, cardiovascular complications should be recognized and treated aggressively to minimize the adverse effects of cancer therapy.

Searching for Evidence to Support the Use of Ginger in the Prevention of Chemotherapy-Induced Nausea and Vomiting.

Patients with cancer frequently use dietary supplementation and herbal therapies to control symptoms of disease and adverse effects of cancer therapy. Despite the widespread use of dietary supplementation and herbal therapies in oncology, robust scientific evidence in this area is lacking. Not only do these products need to be tested in large and well-designed observational or randomized studies, but their manufacturing process must be improved to achieve higher levels of standardization in product quality. Ginger is frequently used to counteract chemotherapy-induced nausea and vomiting (CINV), and some suggestions that it might be effective against CINV come from randomized and/or crossover clinical trials. However, several limitations in the methods of these studies limit their power and generalizability. The authors are conducting a randomized, double-blind study with a large sample size and homogeneous inclusion criteria in order to evaluate the efficacy of a well-standardized ginger extract in reducing nausea in patients with cancer. The widespread use of standardized herbal therapies and natural components among patients requires that scientific and rigorous research strategies are applied in this field to guide the physicians and the patients in safer use.

ACOG Committee Opinion No. 659 Summary: The Use of Vaginal Estrogen in Women With a History of Estrogen-Dependent Breast Cancer.

Cancer treatment should address female-specific survivorship issues, including the hypoestrogenic- related adverse effects of cancer therapies or of natural menopause in survivors. Systemic and vaginal estrogen are widely used for symptomatic relief of vasomotor symptoms, sexual dysfunction, and lower urinary tract infections in the general population. However, given that some types of cancer are hormone sensitive, there are safety concerns about the use of local hormone therapy in women who currently have breast cancer or have a history of breast cancer. Nonhormonal approaches are the first-line choices for managing urogenital symptoms or atrophy-related urinary symptoms experienced by women during or after treatment for breast cancer. Among women with a history of estrogen-dependent breast cancer who are experiencing urogenital symptoms, vaginal estrogen should be reserved for those patients who are unresponsive to nonhormonal remedies. The decision to use vaginal estrogen may be made in coordination with a woman's oncologist. Additionally, it should be preceded by an informed decision-making and consent process in which the woman has the information and resources to consider the benefits and potential risks of low-dose vaginal estrogen. Data do not show an increased risk of cancer recurrence among women currently undergoing treatment for breast cancer or those with a personal history of breast cancer who use vaginal estrogen to relieve urogenital symptoms.

ACOG Committee Opinion No. 659: The Use of Vaginal Estrogen in Women With a History of Estrogen-Dependent Breast Cancer.

Cancer treatment should address female-specific survivorship issues, including the hypoestrogenic- related adverse effects of cancer therapies or of natural menopause in survivors. Systemic and vaginal estrogen are widely used for symptomatic relief of vasomotor symptoms, sexual dysfunction, and lower urinary tract infections in the general population. However, given that some types of cancer are hormone sensitive, there are safety concerns about the use of local hormone therapy in women who currently have breast cancer or have a history of breast cancer. Nonhormonal approaches are the first-line choices for managing urogenital symptoms or atrophy-related urinary symptoms experienced by women during or after treatment for breast cancer. Among women with a history of estrogen-dependent breast cancer who are experiencing urogenital symptoms, vaginal estrogen should be reserved for those patients who are unresponsive to nonhormonal remedies. The decision to use vaginal estrogen may be made in coordination with a woman's oncologist. Additionally, it should be preceded by an informed decision-making and consent process in which the woman has the information and resources to consider the benefits and potential risks of low-dose vaginal estrogen. Data do not show an increased risk of cancer recurrence among women currently undergoing treatment for breast cancer or those with a personal history of breast cancer who use vaginal estrogen to relieve urogenital symptoms.

Limitations of N-Terminal Pro-B-Type Natriuretic Peptide in the Diagnosis of Heart Disease among Cancer Patients Who Present with Cardiac or Pulmonary Symptoms

Objectives: Recognizing heart disease is relevant to oncologists because cancer patients are at an increased risk of cardiac mortality due to shared risk factors and the adverse effects of cancer therapy. This study assessed the extent to which the measurement of N-terminal pro-B-type natriuretic peptide (NT-proBNP) aids in the diagnosis of heart disease in addition to a history of coronary artery disease and the presence of atrial fibrillation (composite test). The NT- proBNP cutoff value was 100 pg/ml. Methods: A series of 583 consecutive cancer patients (68.4 ± 11.0 years) who were referred because of cardiac or pulmonary symptoms prospectively underwent a diagnostic work-up. Heart disease was diagnosed if at least one of the following conditions was present: (a) history of coronary artery disease, (b) atrial fibrillation, (c) impaired left ventricular systolic function, (d) significant valvular disease, (e) pulmonary hypertension, or (f) left ventricular hypertrophy. Results: Except for (a), all 6 conditions were associated with NT-proBNP >100 pg/ml. The sensitivity/specificity values of the composite test were 0.92/0.50 for any heart disease. Several extracardiac covariates were associated with NT-proBNP >100 pg/ml, which contributed to the low test specificity. Conclusions: The low specificity of NT-proBNP limits its value for the diagnosis of heart disease in cancer patients.

Improving prediction of cardiovascular complications of cancer therapy: what does the future hold?

In the era of improved cancer outcomes, increased therapeutic options, and growing population of cancer survivors, the acute and long-term adverse effects of cancer therapies are becoming increasingly relevant. Improved tools for cardiovascular (CV) risk prediction may allow physicians to better tailor cancer therapy, identify patients who would benefit from close CV monitoring and consider CV protective approaches prior, during and after cancer treatment. Ongoing major advances in oncology therapeutics, with vast repertoire of new molecules targeting key tumor pathways, have brought unprecedented opportunities to combat cancer and occasionally manifested unexpected CV side effects pointing to important, unexplored interactions between new therapeutics and CV homeostasis. Probably most widely known example is the one of trastuzumab, HER2targeted monoclonal antibody used in the treatment of HER2-positive breast cancer, that can cause left ventricular (LV) dysfunction and heart failure in susceptible individuals [1,2]. Major strides have been made to limit CV toxicity of trastuzumab and related new HER2-targeted agents, pertuzumab and ado-trastuzumab emtansine, including mandatory assessment of cardiac function prior and during treatment with HER2-targeted agents, and holding or stopping therapy in patients with abnormal LV systolic function [3–5]. These clinical practice recommendations evolved from clinical trial experiences and represent an important step forward in recognizing and limiting cardiotoxicity or HER2-targeted therapies, nevertheless a number of questions continue to challenge daily clinical practice. They include the concerns that stopping and holding HER2-therapy in patients whose cardiac function is only mildly reduced may compromise their cancer outcomes (to improve what may be a low cardiac risk). On the other side of the coin are the patients with normal cardiac function at baseline who continue to experience cardiotoxicity and OpiniOn Special Focus Issue: Cardio-oncology

SP-0009: Uncomplicated cures - a paradigm shift in cancer survivorship research

Changes in cancer incidence and mortality have been modest during the past several decades, but the number of cancer survivors has almost tripled during the same period. With the increasing cohort of cancer survivors, efforts to prevent, diagnose and manage adverse effects of cancer therapy, in general, and those of radiation therapy specifically, have intensified. Considerable progress towards reducing toxicity of radiation therapy has been achieved by the introduction of so-called dose-sculpting treatment techniques. Moreover, new insights into the underlying pathophysiology have resulted in an improved understanding of mechanisms of radiation-induced normal tissue toxicity and in development of new diagnostic strategies and management opportunities. However, the risk of normal tissue toxicity still limits the dose of cytotoxic therapy that can be given, thus limiting the curability of cancer. The steadily increasing number of cancer survivors and the demand for uncomplicated cancer cures require a paradigm shift in cancer survivorship research. Research must shift from simply describing and palliating side effects (“doing head-counts”) to adopt a more modern, goal-oriented approach. The new approach encompasses 1) epidemiological, psychosocial, and outcomes research aimed at characterizing and ameliorating the problems that afflict current cancer survivors; 2) applied clinical and preclinical research aimed at developing new treatments or response modifiers to prevent or minimize shortand longterm side effects of cancer therapy; and 3) basic research aimed at improving our understanding of the cellular and molecular mechanisms that are responsible for treatmentrelated toxicities. This three-pronged approach will ensure that progress is made toward our ultimate goal, i.e., to increase the uncomplicated cancer cure rate.

Doxorubicin-loaded glycyrrhetinic acid modified recombinant human serum albumin nanoparticles for targeting liver tumor chemotherapy.

Due to overexpression of glycyrrhetinic acid (GA) receptor in liver cancer cells, glycyrrhetinic acid modified recombinant human serum albumin (rHSA) nanoparticles for targeting liver tumor cells may result in increased therapeutic efficacy and decreased adverse effects of cancer therapy. In this study, doxorubicin (DOX) loaded and glycyrrhetinic acid modified recombinant human serum albumin nanoparticles (DOX/GA-rHSA NPs) were prepared for targeting therapy for liver cancer. GA was covalently coupled to recombinant human serum albumin nanoparticles, which could efficiently deliver DOX into liver cancer cells. The resultant GA-rHSA NPs exhibited uniform spherical shape and high stability in plasma with fixed negative charge (∼-25 mV) and a size about 170 nm. DOX was loaded into GA-rHSA NPs with a maximal encapsulation efficiency of 75.8%. Moreover, the targeted NPs (DOX/GA-rHSA NPs) showed increased cytotoxic activity in liver tumor cells compared to the nontargeted NPs (DOX/rHSA NPs, DOX loaded recombinant human serum albumin nanoparticles without GA conjugating). The targeted NPs exhibited higher cellular uptake in a GA receptor-positive liver cancer cell line than nontargeted NPs as measured by both flow cytometry and confocal laser scanning microscopy. Biodistribution experiments showed that DOX/GA-rHSA NPs exhibited a much higher level of tumor accumulation than nontargeted NPs at 1 h after injection in hepatoma-bearing Balb/c mice. Therefore, the DOX/GA-rHSA NPs could be considered as an efficient nanoplatform for targeting drug delivery system for liver cancer.