Shuang Cai

University of Kansas, Lawrence, Kansas, United States

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Publications (21)53.3 Total impact

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    ABSTRACT: Abstract Background: Hyaluronan (HA) is a ligand for the CD44 receptor which is crucial to cancer cell proliferation and metastasis. High levels of CD44 expression in many cancers have encouraged the development of HA-based carriers for anti-cancer therapeutics. Purpose: The objective of this study was to determine whether HA conjugation of anticancer drugs impacts CD44-specific HA-drug uptake and disposition by human head and neck cancer cells. Methods: The internalization and cellular disposition of hyaluronan-doxorubicin (HA-DOX), hyaluronan-cisplatin (HA-Pt), and hyaluronan-cyanine7 (HA-Cy7) conjugates were investigated by inhibiting endocytosis pathways, and by inhibiting the CD44-mediated internalization pathways that are known to mediate hyaluronan uptake in vitro. Results: Cellular internalization of HA was regulated by CD44 receptors. In mouse xenografts, HA conjugation significantly enhanced tumor cell uptake compared to unconjugated drugs. Discussion: The results suggested that the main mechanism of HA-based conjugate uptake may be active transport via CD44 in conjunction with a clathrin-dependent endocytic pathway. Other HA receptors, hyaluronan-mediated motility receptor (RHAMM) and lymphatic vessel endothelial hyaluronan receptor (LYVE-1), did not play a significant role in conjugate uptake. Conclusions: HA conjugation significantly increased CD44-mediated drug uptake and extended the residence time of drugs in tumor cells.
    Journal of drug targeting. 06/2014;
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    ABSTRACT: Melanoma is a deadly skin cancer with rapidly rising incidence. While localized melanoma can be treated with excision, there are at present no similarly effective treatments for regional and distant disease, so survival rates are low. One problem is that melanoma is chemo-resistant, and most chemotherapy doses are limited by systemic toxicity. A method for delivering high-dose chemotherapy directly to tumors and draining lymph nodes could have the advantage of allowing much higher effective doses with reduced systemic exposure. Human melanoma cell line A-2058 tumor cells were injected into athymic mice. After tumors grew to 50~100 mm3 mice were divided into five groups: (1) nontreated (2) intravenous (i.v.) cisplatin, (3) i.v. nano hyaluronan-conjugated cisplatin (HA-Pt), (4) subcutaneous (s.c.) peri-tumoral cisplatin, and (5) s.c. peri-tumoral HA-Pt. All treatment groups received 3 weekly doses of 10 mg/kg. Tumors grew progressively in all control, i.v. cisplatin, and s.c. cisplatin groups. Tumors showed a trend toward slower growth in the i.v. HA-Pt group, but all animals died or were euthanized per protocol within 3 weeks of treatment. Tumors showed shrinkage only in the subcutaneous peri-tumoral HA-cisplatin group; one of these mice appeared to be cured. Peri-tumoral HA-cisplatin may be shown potential as a therapeutic option in treatment of certain types of melanoma. J Drugs Dermatol. 2014;13(3):283-287.
    Journal of drugs in dermatology: JDD 03/2014; 13(3):283-7. · 1.16 Impact Factor
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    ABSTRACT: IMPORTANCE Treatment of locally advanced head and neck squamous cell carcinoma (HNSCC) uses a multidisciplinary approach often limited by the toxicity and drug resistance of platinum agents. OBJECTIVES To test whether a nanocarrier-conjugated cisplatin boosting locoregional drug delivery improves tumor efficacy while decreasing systemic toxicity over systemic cisplatin in a murine model of locally advanced HNSCC. DESIGN A randomized, controlled, in vivo study compared standard cisplatin with nanocarrier (hyaluronan [HA])-conjugated cisplatin (HA-cisplatin) each at 50% of the maximum tolerated doses in a murine model of locally advanced HNSCC (10 mice/arm, each injected with 1 × 106 MDA-1986 HNSCC cells, with phosphate-buffered saline and HA-only control arms). Mice were treated for 3 weeks and observed for 3 additional weeks. SETTING Academic medical center. PARTICIPANTS Forty female Nu/Nu mice. Randomization and treatment arms were initiated once tumor volumes reached 30 mm3. INTERVENTION Injection with MDA-1986 HNSCC cells followed by 3 weeks of treatment with cisplatin, HA-cisplatin, phosphate-buffered saline, or HA only. MAIN OUTCOMES AND MEASURES Animal weights and tumor volumes were measured 3 times each week (modified RECIST [Response Evaluation Criteria in Solid Tumors]). At necropsy, animal kidneys were examined for nephrotoxic effects and cochleae were examined for ototoxic effects. RESULTS The mice treated with HA-cisplatin showed superior tumor efficacy (1 with complete clinical response, 3 with partial response, 1 with stable disease, and 5 with progressive disease) compared with standard cisplatin (no animals with complete clinical response, 1 with partial response, 1 with stable disease, and 8 with progressive disease), which was statistically significant (P = .003). All control animals developed progressive disease. Weight loss and body score were surrogate measures of treatment toxicity. The HA-cisplatin group had the least weight loss (mean [SD], 10.8% [4.7%]) compared with the cisplatin group (13.6% [5.6%]; P = .25). Body score dropped to 2 or less in all cisplatin-treated mice but not in any HA-cisplatin-treated mice, which also lacked any histologic signs of nephrotoxic or ototoxic effects. CONCLUSIONS AND RELEVANCE Nanoconjugated HA-cisplatin significantly improves tumor efficacy with lower toxicity compared with standard cisplatin in locally advanced HNSCC in vivo, justifying additional translational studies.
    JAMA otolaryngology-- head & neck surgery. 04/2013; 139(4):382-387.
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    ABSTRACT: Objective-To determine the effects of intratumoral injection of a hyaluronan-cisplatin nanoconjugate on local and systemic platinum concentrations and systemic toxicosis. Animals-5 dogs with spontaneous soft tissue sarcomas (STSs). Procedures-For each dog, approximately 1.5 mL of hyaluronan nanocarrier conjugated with 20 mg of cisplatin was injected into an external STS. Blood samples were collected immediately before (0 hours) and at 0.5, 1, 2, 3, 4, 24, and 96 hours after hyaluronan-cisplatin injection for pharmacokinetic analyses. Urine samples were obtained at 0 and at 96 hours after hyaluronan-cisplatin injection for urinalysis. Each treated STS and its sentinel lymph nodes were surgically removed 96 hours after the hyaluronan-cisplatin injection. Inductively coupled plasma mass spectrometry was used to measure platinum concentrations in blood samples, tumors, and lymph nodes. Results-No tissue reactions were detected 96 hours after hyaluronan-cisplatin injection. Mean ± SD area under the curve, peak concentration, and terminal half-life for unbound (plasma) and total (serum) platinum were 774.6 ± 221.1 ng•h/mL and 3,562.1 ± 2,031.1 ng•h/mL, 56.5 ± 20.9 ng/mL and 81.6 ± 40.4 ng/mL, and 33.6 ± 16.1 hours and 51.2 ± 29.1 hours, respectively. Platinum concentrations ranged from 3,325 to 8,229 ng/g in STSs and 130 to 6,066 ng/g in STS-associated lymph nodes. Conclusions and Clinical Relevance-Intratumoral injection of the hyaluronan-cisplatin nanoconjugate was well tolerated in treated dogs. Following intratumoral hyaluronan-cisplatin injection, platinum concentration was 1,000-fold and 100-fold greater within treated tumors and tumor-draining lymphatics, respectively, compared with that in plasma.
    American Journal of Veterinary Research 12/2012; 73(12):1969-76. · 1.35 Impact Factor
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    ABSTRACT: Functionalized polymeric nanocarriers have been recognized as drug delivery platforms for delivering therapeutic concentrations of chemotherapies. Of this category, star-shaped multiarm polymers are emerging candidates for targeted delivery of anticancer drugs, due to their compact structure, narrow size distribution, large surface area, and high water solubility. In this study, we synthesized a multiarm poly(acrylic acid) star polymer via macromolecular design via the interchange (MADIX)/reversible addition fragmentation chain transfer (MADIX/RAFT) polymerization and characterized it using nuclear magnetic resonance (NMR) and size exclusion chromatography. The poly(acrylic acid) star polymer demonstrated excellent water solubility and extremely low viscosity, making it highly suited for targeted drug delivery. Subsequently, we selected a hydrophilic drug, cisplatin, and a hydrophobic nitric oxide (NO)-donating prodrug, O2-(2,4-dinitrophenyl) 1-[4-(2-hydroxy)ethyl]-3-methylpiperazin-1-yl]diazen-1-ium-1,2-diolate, as two model compounds to evaluate the feasibility of using poly(acrylic acid) star polymers for the delivery of chemotherapeutics. After synthesizing and characterizing two poly(acrylic acid) star polymer-based nanoconjugates, poly(acrylic acid)–cisplatin (acid–Pt) and poly(acrylic acid–NO (acid–NO) prodrug, the in vitro drug release kinetics of both the acid–Pt and the acid–NO were determined at physiological conditions. In summary, we have designed and evaluated a polymeric nanocarrier for sustained-delivery of chemotherapies, either as a single treatment or a combination therapy regimen. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012
    Journal of Polymer Science Part A Polymer Chemistry 07/2012; 50(13):2715-2724. · 3.54 Impact Factor
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    ABSTRACT: Targeted lymphatic delivery of nanoparticles for drug delivery and imaging is primarily dependent on size and charge. Prior studies have observed increased lymphatic uptake and retentions of over 48 h for negatively charged particles compared to neutral and positively charged particles. We have developed new polymeric materials that extend retention over a more pharmaceutically relevant 7-day period. We used whole body fluorescence imaging to observe in mice the lymphatic trafficking of a series of anionic star poly-(6-O-methacryloyl-D-galactose) polymer-NIR dye (IR820) conjugates. The anionic charge of polymers was increased by modifying galactose moieties in the star polymers with succinic anhydride. Increasing anionic nature was associated with enhanced lymphatic uptake up to a zeta potential of ca.-40 mV; further negative charge did not affect lymphatic uptake. Compared to the 20% acid-conjugate, the 40-90% acid-star-polymer conjugates exhibited a 2.5- to 3.5-fold increase in lymphatic uptake in both the popliteal and iliac nodes. The polymer conjugates exhibited node half-lives of 2-20 h in the popliteal nodes and 19-114 h in the deeper iliac nodes. These polymer conjugates can deliver drugs or imaging agents with rapid lymphatic uptake and prolonged deep-nodal retention; thus they may provide a useful vehicle for sustained intralymphatic drug delivery with low toxicity.
    European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 04/2012; 47(1):287-94. · 2.61 Impact Factor
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    ABSTRACT: Nitric oxide is a cell signaling molecule that can be a potent inducer of cell death in cancers at elevated concentrations. However, NO is also toxic to normal tissues and chronic exposure at low levels can induce tumor growth. We have designed a polymeric carrier system to deliver nitric oxide locoregionally to tumorigenic tissues at micromolar concentrations. A highly water solubility and biodegradable multi-arm polymer nanocarrier, sugar poly-(6-O-methacryloyl-d-galactose), was synthesized using MADIX/RAFT polymerization, and utilized to deliver high concentrations of nitric oxide to xenografts of human head and neck squamous cell carcinoma (HNSCC). The in vitro release of the newly synthesized nitric oxide donor, O(2)-(2,4-dinitrophenyl) 1-[4-(2-hydroxy)ethyl]-3-methylpiperazin-1-yl]diazen-1-ium-1,2-diolate and its corresponding multi-arm polymer-based nanoconjugate demonstrated a 1- and 2.3-fold increase in half-life, respectively, compared to the release half-life of the nitric oxide-donor prodrug JS-K. When administered to tumor-bearing nude mice, the subcutaneously injected multi-arm polymer nitric oxide nanoparticles resulted in 50% tumor inhibition and a 7-week extension of the average survival time, compared to intravenous JS-K therapy. In summary, we have developed an effective nitric oxide anti-cancer chemotherapy that could be administered regionally to provide the local disease control, improving prognosis for head and neck cancers.
    Biomaterials 04/2012; 33(11):3243-53. · 8.31 Impact Factor
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    ABSTRACT: Anti-cancer drugs typically exert their pharmacological effect on tumors by inducing apoptosis, or programmed cell death, within the cancer cells, with PCD occurring as soon as 4 hours after treatment. Detection of apoptosis in patients could decisively report a response to treatment days or even weeks before MRI, CAT, and ultrasound indicate morphological changes in the tumor. Here we developed a novel near-infrared dye based imaging probe to directly detect apoptosis with high specificity in cancer cells by utilizing a non-invasive photoacoustic imaging technique. Nude mice bearing head and neck tumors received cisplatin chemotherapy were imaged by PAI after tail vein injection of the contrast agent. In vivo PAI indicated a strong apoptotic response to chemotherapy on the peripheral margins of tumors, whereas untreated controls showed no contrast enhancement by PAI. The apoptotic status of the mouse tumor tissue was verified by immunohistochemical techniques staining for cleaved caspase-3 p11 subunit. The results demonstrated the potential of this imaging probe to guide the evaluation of chemotherapy treatment.
    Proc SPIE 02/2012;
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    ABSTRACT: New lymphatic imaging technologies are needed to better assess immune function and cancer progression and treatment. Lymphatic uptake depends mainly on particle size (10-100 nm) and charge. The size of carriers for imaging and drug delivery can be optimized to maximize lymphatic uptake, localize chemotherapy to lymphatic metastases, and enable visualization of treatment deposition. Toward this end, female BALB/c mice were injected subcutaneously in the hind footpad or forearm with a series of six different molecular weight hyaluronan (HA) near-infrared dye (HA-IR820) conjugates (ca. 5-200 nm). Mice were imaged using whole body fluorescent imaging over two weeks. HA-IR820 fluorescence was clearly visualized in the draining lymphatic capillaries, and in the popliteal and iliac or axillary lymph nodes. The 74-kDa HA-IR820 had the largest lymph node area-under-the-curve. In contrast to prior reports, mice bearing limb tumors exhibited three-fold longer retention of 74-kDa HA-IR820 in the popliteal node compared to mice without tumors. HA conjugate kinetics and disposition can be specifically tailored by altering their molecular weight. The specific lymphatic uptake and increased nodal retention of HA conjugates indicate significant potential for development as a natural biopolymer for intralymphatic drug delivery and imaging.
    Pharmaceutics 01/2012; 4(2):276-295.
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    ABSTRACT: Combination cytotoxic agents in breast cancer carry dose-limiting toxicities. The aim of this study was to test the hypothesis that nanocarrier-conjugated doxorubicin and cisplatin would have improved tumor efficacy with decreased systemic toxicity over standard drugs, even at lower doses. Female Nu/Nu mice were injected in the breast with human MDA-MB-468LN cells and treated with either standard or nanocarrier-conjugated combination therapy (doxorubicin plus cisplatin) at 50% or 75% maximum tolerated dose (MTD) and monitored for efficacy and toxicity over 12 weeks. Efficacy results for mice treated with hyaluronan-conjugated doxorubicin and cisplatin at 50% MTD were as follows: 5 complete responses, 2 partial responses, and 1 case of stable disease. For hyaluronan-conjugated doxorubicin and cisplatin at 75% MTD, efficacy results were as follows: 7 complete responses, 1 partial response. All complete responses were confirmed histologically. In comparison, mice given standard doxorubicin and cisplatin at 50% MTD demonstrated progressive disease in 6, stable disease in 1, and partial response in 1. For standard doxorubicin and cisplatin at 75% MTD, there were 5 cases of progressive disease and 3 of stable disease (P < .0001 on multivariate analysis of variance). At 75% MTD, standard drug-treated mice had significant weight loss compared to nanocarrier drug-treated mice (P < .001). Subcutaneous nanocarrier delivery of doxorubicin and cisplatin demonstrated significantly improved efficacy with decreased toxicity compared with standard agent combination therapy at all doses tested, achieving complete pathologic tumor response.
    American journal of surgery 12/2011; 202(6):646-52; discussion 652-3. · 2.36 Impact Factor
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    ABSTRACT: Anti-cancer drugs typically exert their pharmacological effect on tumors by inducing apoptosis, or programmed cell death, within the cancer cells. However, no tools exist in the clinic for detecting apoptosis in real time. Microscopic examination of surgical biopsies and secondary responses, such as morphological changes, are used to verify efficacy of a treatment. Here, we developed a novel near-infrared dye-based imaging probe to directly detect apoptosis with high specificity in cancer cells by utilizing a noninvasive photoacoustic imaging (PAI) technique. Nude mice bearing head and neck tumors received cisplatin chemotherapy (10 mg/kg) and were imaged by PAI after tail vein injection of the contrast agent. In vivo PAI indicated a strong apoptotic response to chemotherapy on the peripheral margins of tumors, whereas untreated controls showed no contrast enhancement by PAI. The apoptotic status of the mouse tumor tissue was verified by immunohistochemical techniques staining for cleaved caspase-3 p11 subunit. The results demonstrated the potential of this imaging probe to guide the evaluation of chemotherapy treatment.
    Journal of Biomedical Optics 11/2011; 16(11):116026. · 2.88 Impact Factor
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    ABSTRACT: Conventional oral and intravenous chemotherapies permeate throughout the body, exposing healthy tissues to similar cytotoxic drug levels as tumors. This leads to significant dose-limiting toxicities that may prevent patients from receiving sufficient treatment to overcome cancers. Therefore, a number of locoregional drug-delivery strategies have been evaluated and implemented in preclinical studies, clinical trials and in practice, in the past decades to minimize systemic toxicities from chemotherapeutic agents and to improve treatment outcomes. Localized treatment is beneficial because many cancers, such as melanoma, peritoneal cancer and breast cancer, advance locally adjacent to the site of the primary tumors prior to their circulatory invasion. In this article, we will review the feasibility, safety and efficacy of multiple localized chemotherapies in clinical use and preclinical development.
    Therapeutic delivery 11/2011; 2(11):1467-84.
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    ABSTRACT: The lymphatic system plays a crucial role in the immune system's recognition and response to disease, and most solid cancers initially spread from the primary site via the tumor's surrounding lymphatics before hematological dissemination. Hence, the lymphatic system is an important target for developing new vaccines, cancer treatments, and diagnostic agents. Targeting the lymphatic system by subcutaneous, intestinal, and pulmonary routes has been evaluated and subsequently utilized to improve lymphatic penetration and retention of drug molecules, reduce drug-related systemic toxicities, and enhance bioavailability of poorly soluble and unstable drugs. Lymphatic imaging is an essential tool for the detection and staging of cancer. New nano-based technologies offer improved detection and characterization of the nodal diseases, while new delivery devices can better target and confine treatments to tumors within the nodal space while sparing healthy tissues. This manuscript reviews recent advances in the field of lymphatic drug delivery and imaging and focuses specifically on the development of liposomes and solid lipid nanoparticles for lymphatic introduction via the subcutaneous, intestinal, and pulmonary routes.
    Advanced drug delivery reviews 06/2011; 63(10-11):901-8. · 11.96 Impact Factor
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    ABSTRACT: Near-infrared (NIR) absorbing dyes represent an intriguing avenue for extracting biological information from living subjects since they can be monitored with noninvasive optical imaging techniques. We designed and synthesized an imaging agent which contains a NIR fluorochrome (IR780) and peptidyl fluoromethyl ketone (FMK) for caspase-9 imaging of cells undergoing apoptosis. The IR780-FMK fluorescent probe had a Strokes shift of 79 nm and quantum yield 0.75. Prostate cancer DU145 cells undergoing apoptosis were successfully imaged using as little as 0.1 μM of IR780-FMK.
    Drug discoveries & therapeutics. 01/2011; 5(5):220-226.
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    ABSTRACT: Patients with metastatic breast cancer have a five-year survival rate of 27% compared to 98% for localized cancer, and the presence of even a few cancer cells in lymph nodes, known as isolated tumor cells or nanometastases, significantly increases the risk of relapse in the absence of aggressive treatment. Therefore, diagnosis and treatment of lymphatic metastases in early breast cancer plays an important role in patient survival. Here, we demonstrate the first description of a delivery system for localized doxorubicin chemotherapy to the breast tissue. The hyaluronan-doxorubicin nanoconjugate exhibits a sustained release characteristic in vitro and in vivo in the breast tissues of rodents bearing human breast cancer xenografts. In addition, the conjugate reduces dose-limiting cardiac toxicity with minimal toxicity observed in normal tissues. Finally, the conjugate dramatically inhibits breast cancer progression in vivo, leading to an increased survival rate. Thus, localized chemotherapy to the breast lymphatics with a nanocarrier may represent an improved strategy for treatment of early stage breast cancers.
    Journal of Controlled Release 09/2010; 146(2):212-8. · 7.63 Impact Factor
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    ABSTRACT: Since head and neck squamous cell carcinoma (HNSCC) preferentially metastasizes to the locoregional lymphatics, treatment of the tumor-draining cervical lymph nodes is paramount. We developed a hyaluronan-cisplatin (HA-Pt) nanoconjugate with prolonged lymphatic retention and greatly improved tumor tissue deposition for the treatment of metastatic HNSCC. We also developed an orthotopic metastatic xenograft model of HNSCC to examine the efficacy of the nanoconjugate. HNSCC (1/week x 3 weeks) were completely cured for 57% of the female mice in the HA-Pt treatment group, which demonstrated greatly hindered HNSCC progression compared with the standard cisplatin therapy (p < 0.05). With this insight, we will be able to optimize the carriers for better uptake, penetration and retention within cancer cells.
    Therapeutic delivery 08/2010; 1(2):237-45.
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    ABSTRACT: Cisplatin (CDDP) intravenous treatments suffer several dose-limiting toxicity issues. Hyaluronan (HA), a naturally occurring biopolymer in the interstitium, is primarily cleared by the lymphatic system. An alteration in input rate and administration route through pulmonary delivery of hyaluronan-cisplatin (HA-Pt) conjugate may increase local lung CDDP concentrations and decrease systemic toxicity. Sprague-Dawley rats were split into four groups: i.v. CDDP (3.5 mg/kg), i.v. HA-Pt conjugate (3.5 mg/kg equivalent CDDP), lung instillation CDDP and lung instillation HA-Pt conjugate. Total platinum level in the lungs of the HA-Pt lung instillation group was 5.7-fold and 1.2-fold higher than the CDDP intravenous group at 24 and 96 h, respectively. A 1.1-fold increase of Pt accumulation in lung draining nodes for the HA-Pt lung instillation group was achieved at 24h relative to the CDDP i.v. group. In the brain and kidneys, the CDDP i.v. group had higher tissue/plasma ratios compared to the HA-Pt lung instillation group. Augmented tissue distribution from CDDP i.v. could translate into enhanced tissue toxicity compared to the altered input rate and distribution of the intrapulmonary nanoformulation. In conclusion, a local pulmonary CDDP delivery system was developed with increased platinum concentration in the lungs and draining nodes compared to i.v. therapy.
    International Journal of Pharmaceutics 04/2010; 392(1-2):156-63. · 3.99 Impact Factor
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    ABSTRACT: Cisplatin (CDDP) is an effective anticancer agent for many solid tumors but has significant systemic toxicity limiting its use in many patients. We have designed a loco-regional delivery system to increase platinum levels in the lymphatics, where early metastasis is most likely to occur, while reducing systemic toxicities. CDDP was conjugated to a biocompatible polymer hyaluronan (HA), with a conjugation degree of approximately 20% (w/w). Conjugates were delivered via subcutaneous injection into the mammary fat pad of rats. Intravenous hyaluronan-cisplatin (HA-Pt) exhibited an increased plasma area under the curve (AUC) 2.7-fold compared to conventional CDDP but with a reduced peak plasma level (C(max)), and HA-Pt increased the ipsilateral lymph node AUC by 3.8-fold compared to CDDP. Urine creatinine was unchanged over 30 days following dosing of HA-Pt. This study demonstrates that intralymphatic drug delivery with polymer-conjugated platinum may provide greater tissue and systemic plasma concentrations of platinum than intravenous CDDP. In addition, localized particle delivery augmented distribution in the loco-regional tissue basin where tumor burden predominates, while renal toxicity compared to standard intravenous CDDP was significantly reduced.
    Journal of Pharmaceutical Sciences 12/2009; 99(6):2664-71. · 3.13 Impact Factor
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    ABSTRACT: A lymphatically delivered nanoconjugate of cisplatin was evaluated in an orthotopic mouse model of locoregionally metastatic breast cancer (LABC) to determine if it can overcome some of the limitations of standard cisplatin therapy such as high systemic toxicity. Human breast cancer cells (10(7) MDA-MB-468LN) were injected into the mammary fat pad of female nu/nu mice. Once tumor volume reached 50 mm(3), intravenous cisplatin or subcutaneous hyaluronan-cisplatin (HA-cisplatin) nanoconjugate was given 1/week x 3 weeks at 3.3 mg/kg (platinum basis). Nanoconjugates colocalized with the tumors after subcutaneous peritumoral injection and showed improved efficacy to intravenous cisplatin. After 1 month, renal tubular hemorrhage and edema were more prevalent in the intravenous formulation compared with subcutaneous HA-cisplatin nanoconjugates. This nanocarrier delivery platform focuses on delivering drugs to the areas in which tumor burden is greatest, potentially reducing systemic toxicity, and has future applicability as a neoadjuvant or adjuvant therapy for LABC.
    American journal of surgery 12/2009; 198(6):781-6. · 2.36 Impact Factor
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    ABSTRACT: Breast cancers typically spread to regional lymph nodes once they disseminate from the primary tumor, thus adequate evaluation and treatment of the axillary lymph nodes is paramount in early stage disease. One significant problem with current therapy is the side effects chemotherapy agents create systemically, either alone or in combination. The purpose of this study is to determine whether lymphatically targeted cisplatin carriers will increase the localized dose in lymphatic metastases without systemic toxicities. Hyaluronan (HA) is a highly biocompatible polymer that follows lymphatic drainage from the interstitial spaces. We formed complexes of HA and cisplatin by non-covalent conjugation. Complexes were injected subcutaneously into the upper mammary fat pad of female rats, and the tissue distribution determined. Cisplatin-HA contained up to 0.25 w/w of Pt and released drug with a half-life of 10 h in saline. Cisplatin-HA conjugates had high anti-tumor activity in vitro similar to the free drug: cisplatin-HA IC50 7 microg/mL in MCF7 and MDA-MB-231 human breast cancer cells (free cisplatin IC50 7 microg/mL). Cisplatin-HA conjugates were well tolerated in rodents with no signs of injection site morbidity or major organ toxicity after 96 h. The area-under-the-curve of cisplatin in the axially lymph nodes after injection with cisplatin-HA increased 74% compared with normal cisplatin. This study demonstrates a novel intralymphatic drug delivery method in breast cancer to preferentially treat at-risk regional lymph nodes and avoid systemic toxicities. Further in vivo testing related to efficacy of this approach with regard to survival, toxicity, and pharmacokinetics is warranted to support its use in human trials.
    Journal of Surgical Research 07/2008; 147(2):247-52. · 2.02 Impact Factor