Deep Learning-Based Artificial Intelligence to Investigate Targeted Nanoparticles' Uptake in TNBC Cells.

Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer in women. It has the poorest prognosis along with limited therapeutic options. Smart nano-based carriers are emerging as promising approaches in treating TNBC due to their favourable characteristics such as specifically delivering different cargos to cancer cells. However, nanoparticles' tumour cell uptake, and subsequent drug release, are essential factors considered during the drug development process. Contemporary qualitative analyses based on imaging are cumbersome and prone to human biases. Deep learning-based algorithms have been well-established in various healthcare settings with promising scope in drug discovery and development. In this study, the performance of five different convolutional neural network models was evaluated. In this research, we investigated two sequential models from scratch and three pre-trained models, VGG16, ResNet50, and Inception V3. These models were trained using confocal images of nanoparticle-treated cells loaded with a fluorescent anticancer agent. Comparative and cross-validation analyses were further conducted across all models to obtain more meaningful results. Our models showed high accuracy in predicting either high or low drug uptake and release into TNBC cells, indicating great translational potential into practice to aid in determining cellular uptake at the early stages of drug development in any area of research.

Nanotechnology-based platforms to improve immune checkpoint blockade efficacy in cancer therapy.

In recent years, cancer immunotherapy has evolved as an exciting novel strategy for researchers and clinicians worldwide. Immunotherapeutic agents such as immune checkpoint blockers have changed the standard-of-care treatment provided for many tumors. Unfortunately, only a small proportion of patients respond effectively to these checkpoint inhibitors. Moreover, the immunosuppressive pathways for cancer are probably too complicated to achieve optimal outcome with immune checkpoint inhibitors alone. Combining current therapeutic options and immunotherapy-based approaches is being explored as an effective strategy to treat cancer. The use of nanotechnology-based platforms for delivery of immunotherapeutic agents or combination therapy could offer a major advantage over conventional anticancer treatment options. This review highlights the potential role of different nanotechnology-based strategies in improving the efficacy of immune checkpoint blockade therapy.

Bisphosphonate-functionalized micelles for targeted delivery of curcumin to metastatic bone cancer.

Metastatic (secondary) bone cancer is one of the major causes of death in patients with advanced cancer. A lack of options for the targeted delivery of a desired therapeutic payload to multiple tumour modules located in the bone is still one of the foremost hurdles in the treatment/prevention of metastatic bone cancer. Curcumin has a proven anticancer potential with known challenges for application as a pharmaceutical agent. We have previously shown that micellar formulations could overcome some of these challenges and enhances its anti-cancer activity. In this study, we have developed a targeted drug delivery system using bisphosphonate (alendronate) conjugated Pluronic F127 micelles that could efficiently target, and specifically deliver curcumin to the osteolytic tumour microenvironment in the bone. Characterization of the formulation of curcumin-encapsulated alendronate-conjugated micelles demonstrated that the micelles have nanoscale size (∼27 nm) with a positive surface charge (+2.87 mV) and 4% drug loading. The alendronate-conjugated micelles showed significant bone-targeting potential. Rapid binding of the micelles to hydroxyapatite surface suggested that these nanoparticles are promising carriers for effective and targeted delivery of curcumin to osteolytic tumours in the bone.

A study on liposomal encapsulation of a lipophilic prodrug of LHRH.

This study aimed at evaluating whether derivatization of luteinizing hormone-releasing hormone (LHRH) peptide with an amphiphilic lipoamino acid moiety could allow, along with other technological and/or pharmacokinetic advantages, to improve its encapsulation in liposomes, potentially driving its further body distribution and cellular uptake. Experimental data confirmed that a lipophilic derivative of LHRH was efficiently incorporated in various liposomal systems, differing in lipid composition and surface charge, and obtained using different methods of production. Incubation of liposomes, loaded with a fluorescent derivative of the LHRH prodrug, with NCTC keratinocytes or Caco-2 cell cultures showed that the carriers can be rapidly internalized. Conversely, the internalization of the free prodrug occurred only at very high concentrations.

Stability, permeability and growth-inhibitory properties of gonadotropin-releasing hormone liposaccharides.

PURPOSE: In this study we aimed to address the poor drug-like properties of Gonadotropin-Releasing Hormone (GnRH) peptide through modification with lipids and carbohydrates. METHODS: GnRH peptide was conjugated to 2-amino-D,L-octanoic acid (C8) and 2-amino-D,L-dodecanoic acid (C12) in monomer and dimer, along with (6-9) or without (2-5 and 11) a glucose moiety. Peptides were tested for their biological activity using different tumour cell lines. The toxicity of the constructs was evaluated in peripheral blood mononuclear cells (PBMC). RESULTS: All (glyco)lipopeptides showed improved metabolic stability in Caco-2 cell homogenates. Those with single lipid moiety (2, 4 and 8) exhibited prodrug-like properties. Permeability across Caco-2 cell monolayers was enhanced in the dimer C8-modified (glyco)lipopeptide (3) and the lipopeptide with C12 inserted mid-sequence (11). Most of the constructs showed moderate-to-high antiproliferative activity against GnRH-receptor positive DU145 and OVCAR-3 cells (up to 60%). Compound 11 was the most effective with IC50 = 26.4 ± 1.07 µg.ml(-1), which was comparable to triptorelin (25.1 ± 1.14 µg.mL(-1)). The sensitivity of OVCAR-3 cells to the effect of all analogues except for 11 decreased significantly in estrogen-reconstituted media. Only compounds 2, 4, 5 and 8 showed a steroid-dependent effect in DU145 cells. No compounds exhibited significant toxicity on PBMCs. CONCLUSION: These results indicated lipidation and glycosylation improves the druggability of GnRH and could lead to an increased direct antitumour activity in some hormone dependent and independent reproductive cancers.

Active immunisation of mice with GnRH lipopeptide vaccine candidates: Importance of T helper or multi-dimer GnRH epitope.

Active immunisation against gonadotropin releasing hormone (GnRH) is a potential alternative to surgical castration. This study focused on the development of a GnRH subunit lipopeptide vaccine. A library of vaccine candidates that contained one or more (up to eight) copies of monomeric or dimeric GnRH peptide antigen, an adjuvanting lipidic moiety based on lipoamino acids, and an additional T helper epitope, was synthesised by solid phase peptide synthesis. The candidates were evaluated in vivo in order to determine the minimal components of this vaccine necessary to induce a systemic immune response. BALB/c mice were immunised with GnRH lipopeptide conjugates, co-administered with or without Complete Freund's Adjuvant, followed by two additional immunisations. Significant GnRH-specific IgG titres were detected in sera obtained from mice immunised with four of the seven lipopeptides tested, with an increase in titres observed after successive immunisations. This study highlights the importance of for epitope optimisation and delivery system design when producing anti-hapten antibodies in vivo. The results of this study also contribute to the development of future clinical and veterinary immunocontraceptives.

Effect of lipidated gonadotropin-releasing hormone peptides on receptor mediated binding and uptake into prostate cancer cells in vitro.

Gonadotropin-releasing hormone (GnRH) receptors are overexpressed on many cancer cells but not on primary cell lines. This study was designed to investigate the targeting ability and uptake of dendritic lipidated [Gln(1)]-GnRH peptide analogues on receptor-positive prostate cancer PC-3 cells relative to receptor-negative ovarian carcinoma SKOV-3 cells for potential application in drug delivery. Direct antiproliferative effect of these was investigated on three GnRH-receptor positive cancer cells, PC-3, LNCaP and DU145. A significant dose dependent growth inhibitory effect was produced in DU145 cells by 5 dendrimers giving an IC50 value of 22-35 µM. All compounds were non-toxic to the normal peripheral blood mononuclear cells. FROM THE CLINICAL EDITOR: This study demonstrates the use of specific dendritic lapidated GnRH analogues in growth inhibition of GnRH receptor positive prostate cancer cell lines, suggesting potential future clinical use of this or similar strategies to address GnRH receptor positive cancer cells.

Peripherally acting novel lipo-endomorphin-1 peptides in neuropathic pain without producing constipation.

We previously described two novel analogues of endomorphin-1 (Tyr-Pro-Trp-Phe-NH2, 1), modified with an 8-carbon lipoamino acid (C8LAA) with or without replacement of Tyr(1) with 2,6-dimethyltyrosine (Dmt) at the N-terminus of the peptide (compounds 3 and 4, respectively). They were shown to be more stable and permeable, and acted as potent µ-opioid receptor agonists. In this study we report that the C8LAA modification resulted in successful systemic delivery of both analogues. They produced potent dose-dependent pain relief in a chronic constriction injury-rat model of neuropathic pain after intravenous administration with ED50 values obtained at 6.58 (±1.22) µmol/kg for 3 and 6.18 (±1.17) µmol/kg for 4. Using two different rat models of constipation that assess the effects of µ-opioid receptor agonists on stool hydration and gastro-intestinal motility, compound 3 produced insignificant constipation at 16 µmol/kg, whereas morphine elicited significant constipation at 2 µmol/kg. Compound 3 in contrast to morphine, did not attenuate the hypercapnic ventilatory response at 5 µmol/kg, a dose that fully alleviated hindpaw sensitivity at the time of peak effect in CCI-rats. This finding revealed the lack of respiratory depression effect at antinociceptive dose.

Formulation, characterization and permeability study of nano particles of lipo-endomorphin-1 for oral delivery.

Three different formulations of a lipid-modified endomorphin-1 peptide (C10LAA-Endo-1) were prepared, characterized, and evaluated for their permeability through Caco-2 cell membranes. Solid lipid nanoparticles (SLN), enteric coated (EC), and the EC-SLN of C10LAA-Endo-1 is a modified structure of endomorphin-1 for oral delivery. Physico-chemical characterization of the formulations showed that among all formulations, EC-[C10LAA-Endo-1] had the lowest particle size and the highest EE% and absolute zeta potential. Release of drug from SLN, EC-SLN and EC-[C10LAA-Endo-1] in acid media was 14.30 (±2.7)%, 3.0 (±1.0)% and 10.2 (±3.0)%, respectively. Release data in buffer media (pH = 7.4) showed that enteric coated formulations released C10LAA-Endo-1 more slowly than uncoated formulations. It was also demonstrated that direct coating of C10LAA-Endo-1 with Eudragit® S100 significantly enhanced the permeability of the compound through Caco-2 cell membranes with a 39-fold higher P(app) compared to C10LAA-Endo-1. These findings indicated that EC-C10LAA-Endo-1 is a promising candidate to promote the oral delivery of the previously modified endomorphin-1 peptide analogue and is worthy of future animal investigations.

Synthesis, biological activity and structure-activity relationship of endomorphin-1/substance P derivatives.

Endomorphins have been shown to produce potent analgesia in various rodent models of pain. However, their central administration led to the development of tolerance and physical dependence. Conjugation of C-terminal substance P (SP) fragments to opioids and opioid peptides was previously shown to produce hybrid peptides with strong analgesic activity, with low or no propensity to develop tolerance. In this study, four peptides (2-5) comprised of endomorphin-1 (1) and C-terminal fragments of SP (four or five amino acids, SP(8-11) (2) or SP(7-11) (4), respectively), with an overlapping Phe residue, were synthesized. To overcome low metabolic stability and poor membrane permeability of the peptide, the N-terminus of 2 and 4 was further modified with a C10-carbon lipoamino acid (C10LAA) achieving 3 and 5, respectively. LAA-modification of the hybrid peptides resulted in a significant increase in metabolic stability and membrane permeability compared to peptides 1, 2 and 4. Compound 5 showed potent µ-opioid receptor binding affinity (K(iµ)=3.87 ± 0.51 nM) with dose-dependent agonist activity in the nanomolar range (IC(50)=45 ± 13 nM). In silico modeling was used to investigate the binding modes and affinities of compounds 1-5 in the active site of µ-opioid receptors. The docking scores were in agreement with the K(iµ) values obtained in the receptor binding affinity studies. The more active LAA-modified hybrid peptide showed a lower total interaction energy and higher negative value of MolDock score.

Breast Cancer Bone Metastasis: A Narrative Review of Emerging Targeted Drug Delivery Systems.

Bone is one of the most common metastatic sites among breast cancer (BC) patients. Once bone metastasis is developed, patients' survival and quality of life will be significantly declined. At present, there are limited therapeutic options for BC patients with bone metastasis. Different nanotechnology-based delivery systems have been developed aiming to specifically deliver the therapeutic agents to the bone. The conjugation of targeting agents to nanoparticles can enhance the selective delivery of various payloads to the metastatic bone lesion. The current review highlights promising and emerging advanced nanotechnologies designed for targeted delivery of anticancer therapeutics, contrast agents, photodynamic and photothermal materials to the bone to achieve the goal of treatment, diagnosis, and prevention of BC bone metastasis. A better understanding of various properties of these new therapeutic approaches may open up new landscapes in medicine towards improving the quality of life and overall survival of BC patients who experience bone metastasis.

Nanodiamonds and their potential applications in breast cancer therapy: a narrative review.

Breast cancer remains the most commonly diagnosed cancer and the leading cause of cancer-related death among women worldwide. With the projected increase in breast cancer cases in recent years, optimising treatment becomes increasingly important. Current treatment modalities in breast cancer present major limitations, including chemoresistance, dose-limiting adverse effects and lack of selectivity in aggressive subtypes of breast cancers such as triple-negative breast cancer. Nanodiamonds have demonstrated promising outcomes in preclinical models from their unique surface characteristics allowing optimised delivery of various therapeutic agents, overcoming some of the significant hurdles in conventional treatment modalities. This review will present an update on preclinical findings of nanodiamond-based drug delivery systems for breast cancer therapy to date, challenges with the use of nanodiamonds along with considerations for future research.

Potential Nanotechnology-Based Therapeutics to Prevent Cancer Progression through TME Cell-Driven Populations.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with a high risk of metastasis and therapeutic resistance. These issues are closely linked to the tumour microenvironment (TME) surrounding the tumour tissue. The association between residing TME components with tumour progression, survival, and metastasis has been well elucidated. Focusing on cancer cells alone is no longer considered a viable approach to therapy; thus, there is a high demand for TME targeting. The benefit of using nanoparticles is their preferential tumour accumulation and their ability to target TME components. Several nano-based platforms have been investigated to mitigate microenvironment-induced angiogenesis, therapeutic resistance, and tumour progression. These have been achieved by targeting mesenchymal originating cells (e.g., cancer-associated fibroblasts, adipocytes, and stem cells), haematological cells (e.g., tumour-associated macrophages, dendritic cells, and myeloid-derived suppressor cells), and the extracellular matrix within the TME that displays functional and architectural support. This review highlights the importance of nanotechnology-based therapeutics as a promising approach to target the TME and improve treatment outcomes for TNBC patients, which can lead to enhanced survival and quality of life. The role of different nanotherapeutics has been explored in the established TME cell-driven populations.

Temporal evolution, most influential studies and sleeping beauties of the coronavirus literature.

Following the outbreak of SARS-CoV-2 disease, within less than 8 months, the 50 years-old scholarly literature of coronaviruses grew to nearly three times larger than its size prior to 2020. Here, temporal evolution of the coronavirus literature over the last 30 years (N = 43,769) is analysed along with its subdomain of SARS-CoV-2 articles (N = 27,460) and the subdomain of reviews and meta-analytic studies (N = 1027). The analyses are conducted through the lenses of co-citation and bibliographic coupling of documents. (1) Of the N = 1204 review and meta-analytical articles of the coronavirus literature, nearly 88% have been published and indexed during the first 8 months of 2020, marking an unprecedented attention to reviews and meta-analyses in this domain, prompted by the SARS-CoV-2 pandemic. (2) The subset of 2020 SARS-CoV-2 articles is bibliographically distant from the rest of this literature published prior to 2020. Individual articles of the SARS-CoV-2 segment with a bridging role between the two bodies of articles (i.e., before and after 2020) are identifiable. (3) Furthermore, the degree of bibliographic coupling within the 2020 SARS-CoV-2 cluster is much poorer compared to the cluster of articles published prior to 2020. This could, in part, be explained by the higher diversity of topics that are studied in relation to SARS-CoV-2 compared to the literature of coronaviruses published prior to the SARS-CoV-2 disease. (4) The analyses on the subset of SARS-CoV-2 literature identified studies published prior to 2020 that have now proven highly instrumental in the development of various clusters of publications linked to SARS-CoV-2. In particular, the so-called "sleeping beauties" of the coronavirus literature with an awakening in 2020 were identified, i.e., previously published studies of this literature that had remained relatively unnoticed for several years but gained sudden traction in 2020 in the wake of the SARS-CoV-2 outbreak. This work documents the historical development of the literature on coronaviruses as an event-driven literature and as a domain that exhibited, arguably, the most exceptional case of publication burst in the history of science. It also demonstrates how scholarly efforts undertaken during peace time or prior to a disease outbreak could suddenly play a critical role in prevention and mitigation of health disasters caused by new diseases. Supplementary Information: The online version contains supplementary material available at 10.1007/s11192-021-04036-4.

Overcoming Therapy Resistance and Relapse in TNBC: Emerging Technologies to Target Breast Cancer-Associated Fibroblasts.

Breast cancer is the most diagnosed cancer and is the leading cause of cancer mortality in women. Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer. Often, TNBC is not effectively treated due to the lack of specificity of conventional therapies and results in relapse and metastasis. Breast cancer-associated fibroblasts (BCAFs) are the predominant cells that reside in the tumor microenvironment (TME) and regulate tumorigenesis, progression and metastasis, and therapy resistance. BCAFs secrete a wide range of factors, including growth factors, chemokines, and cytokines, some of which have been proved to lead to a poor prognosis and clinical outcomes. This TME component has been emerging as a promising target due to its crucial role in cancer progression and chemotherapy resistance. A number of therapeutic candidates are designed to effectively target BCAFs with a focus on their tumor-promoting properties and tumor immune response. This review explores various agents targeting BCAFs in TNBC, including small molecules, nucleic acid-based agents, antibodies, proteins, and finally, nanoparticles.

New drug delivery strategies targeting the GnRH receptor in breast and other cancers.

Cancer is the uncontrolled division of abnormal cells in a specific organ. Globally, about one in six deaths is due to cancer. Despite the plethora of research being undertaken worldwide to find a cure for cancer, it remains a significant challenge. Cancer targeting via agents designed to interfere with some specifically or highly expressed molecules in cancer cells has been a shift in the treatment of various forms of cancers. The development of drug delivery systems, specifically to cancer cells, is a common approach that succeeded in increasing the efficacy and reducing the side effects of different anticancer agents. Gonadotropin-releasing hormone (GnRH) is a naturally occurring hormone with receptors overexpressed in many types of cancers related or unrelated to the reproductive system. Several drug delivery systems were developed using GnRH derivatives as targeting agents. In this review, we first discuss the role of GnRH and its receptors in cancer. Then, we provide a detailed insight into different delivery systems developed using GnRH derivatives as targeting agents in various types of GnRH receptor overexpressing cancers. Some promising findings from these studies indicate that GnRH receptor targeting is a potential strategy to efficiently guide anticancer therapeutics, diagnostic agents, and nucleic acids directly to cancer cells. Lastly, some limitations of the current research and suggestions for more successful outcomes in clinical trials of these delivery systems are highlighted.

Cytotoxic activity and cell cycle analysis of quinoline alkaloids isolated from Haplophyllum canaliculatum Boiss.

Bioassay-guided fractionation of Haplophyllum canaliculatum Boiss. (Rutaceae) extract resulted in isolation of five quinoline alkaloids: 7-isopentenyloxy-gamma-fagarine, atanine, skimmianine, flindersine and perfamine. This is the first isolation of these compounds from this endemic species. The antitumor activity of these five isolates was evaluated against RAJI, Jurkat, KG-1a, HEP-2, MCF-7, HL-60 and HL-60/MX1 tumor cell lines. The highest cytotoxic effect was observed on acute lymphoblastic leukemia cell lines. 7-Isopentenyloxy-gamma-fagarine, atanine, skimmianine and flindersine exhibited very high cytotoxicity against the RAJI cell line with IC(50) values of 1.5, 14.5, 15.6 and 14.9 microg/mL, respectively and 7-isopentenyloxy-gamma-fagarine, atanine and skimmianine exhibited very high cytotoxicity against the Jurkat cell line with IC(50) values of 3.6, 9.3 and 11.5 microg/mL, respectively. 7-Isopentenyloxy-gamma-fagarine was also highly cytotoxic against the MCF-7 cell line (IC(50) = 15.5 microg/mL), while atanine, skimmianine, flindersine and perfamine showed moderate to low activity against these cells. All alkaloids had moderate to low cytotoxicity against KG-1a and HEP-2. Investigation of the toxic potential of the alkaloids on HL-60 and HL-60/MX1 showed a significantly higher effect against HL-60/MX1, a multidrug-resistant cell line, compared with the control etoposide (p < 0.05). In all cytotoxicity experiments, peripheral blood mononuclear cells (PBMC) were used as a control for normal hematopoietic cells. Flow cytometry analysis of the compounds resulted in the arrest of cell cycle progression at the sub-G1 phase of the RAJI and Jurkat cell lines in a dose-dependent manner. According to computational analyses, the similar cytotoxic trend in the cell lines could be indicative of the fact that these compounds may act through parallel mechanisms.

Theranostic α-Lactalbumin-Polymer-Based Nanocomposite as a Drug Delivery Carrier for Cancer Therapy.

A nanotheranostic system was developed using α-lactalbumin along with Fe3O4 nanoparticles as an magnetic resonance imaging (MRI) contrast agent for medical imaging and doxorubicin as the therapeutic agent. α-lactalbumin was precipitated and cross-linked using poly(ethylene glycol) and glutaraldehyde. Besides, polyethylenimine was applied to increase the number of amine groups during cross-linking between α-lactalbumin and Fe3O4 nanoparticles. Interestingly, 90% of the initial protein used for the coaggregation process was incorporated in the prepared 130 nm nanocomposites, which facilitated the 85% doxorubicin loading. Formation of pH-sensitive imine bonds between glutaraldehyde and amine groups on α-lactalbumin and polyethylenimine resulted in higher release of doxorubicin at acidic pHs and consequently development of a pH-sensitive nanocarrier. The designed nanocomposite was less immunogenic owing to stimulating the production of less amounts of C3a, C5a, platelet factor 4, glycoprotein IIb/IIIa, platelet-derived ß-thromboglobulin, interleukin-6, and interleukin-1ß compared to the free doxorubicin. Furthermore, 1000 µg/mL nanocomposite led to 0.2% hemolytic activity, much less than the 5% standard limit. The void nanocarrier induced no significant level of cytotoxicity in breast cancer and normal cells following 96 h incubation. The doxorubicin-loaded nanocomposite presented higher cytotoxicity, apoptosis induction, and doxorubicin uptake in cancer cells than free doxorubicin. Conversely, lower cytotoxicity, apoptosis induction, and doxorubicin uptake were observed in normal cells treated with the doxorubicin-loaded nanocarrier compared to free doxorubicin. In line with the results of in vitro experiments, in vivo studies on tumor-bearing mice showed more suppression of tumor growth by the doxorubicin-loaded nanocomposite compared to the free drug. Moreover, the pharmacokinetic study revealed slow release of doxorubicin from the nanocomposite. Besides, in vitro and in vivo MRI studies presented a higher r2/r1 ratio and comparable contrast to the commercially available DOTAREM, respectively. Our findings suggest that this new nanocomposite is a promising nanotheranostic system with promising potential for cancer therapy and diagnosis.

Different Targeting Strategies for Treating Breast Cancer Bone Metastases.

BACKGROUND: Breast cancer is the most frequently diagnosed malignancy in women worldwide. Breast cancer tends to metastasize to bone. Around 70% of the breast cancer patients eventually develop bone metastasis. After the bone invasion, metastatic cells disrupt the balance between osteoblastic and osteoclastic activities, leading to skeletal complications, characterized by pain and pathological fractures and hence worsening the patient's quality of life. Once tumor invades the bone, it is hard to treat it with, the so-far available treatments options (e.g. bisphosphonates and denosumab). Bone metastasis should be essentially controlled, in cancer treatment and there is a strong need to explore new, more efficient therapeutic targets. This review discusses the bone physiological processes and the recent advances in exploring different pathways involved in bone metastasis. Furthermore, some novel treatment options, which are under preclinical and clinical investigations, are highlighted. CONCLUSION: A deeper understanding of these metastatic pathways can provide oncology researchers with novel avenues for treating bone metastasis, one of the main challenges to cure breast cancer. The restoration of healthy bone environment will not only improve the patient's quality of life but also reduces the tumor burden.

Development of New Gonadotropin-Releasing Hormone-Modified Dendrimer Platforms with Direct Antiproliferative and Gonadotropin Releasing Activity.

Gonadotropin-releasing hormone (GnRH) agonists (e.g., triptorelin) are used for androgen suppression therapy. They possess improved stability as compared to the natural GnRH, yet they suffer from a poor pharmacokinetic profile. To address this, we used a GnRH peptide-modified dendrimer platform with and without lipidation strategy. Dendrimers were synthesized on a polylysine core and bore either native GnRH (1, 2, and 5) or lipid-modified GnRH (3 and 4). Compound 3, which bore a lipidic moiety in a branched tetramer structure, showed approximately 10-fold higher permeability and metabolic stability and 39 times higher antitumor activity against hormone-resistant prostate cancer cells (DU145) relative to triptorelin. In gonadotropin-release experiments, dendrimer 3 was shown to be the most potent construct. Dendrimer 3 showed similar luteinizing hormone (LH)-release activity to triptorelin in mice. Our findings indicate that dendrimer 3 is a promising analog with higher potency for the treatment of hormone-resistant prostate cancer than the currently available GnRH agonists.